Phenyl urea and phenyl thiourea derivatives as HFGAN72 antagonists

ABSTRACT

Phenyl urea and phenylthiourea derivatives, processes for their production and their uses as pharmaceuticals are disclosed.

This application is a §371 of PCT/GB98/02437, filed Aug. 13, 1998.

This invention relates to phenyl urea and phenyl thiourea derivativesand their use as pharmaceuticals

It is well established that many medically significant biologicalprocesses are mediated by proteins participating in signal transductionpathways that involve G-proteins and/or second messengers, e.g. cAMP(Letkowitz, Nature, 1991, 351:353-354). Examples of these proteinsinclude the GPC receptors, such as those for adrenergic agents anddopamine (Kobilka B. K. et al, Proc. Natl Acad Sci., USA, 1987,84:46-50; Kobila B. K. et at, Science, 1987, 238:650-656; Bunzow, J. R.et al, Nature, 1988, 336:783-787), G-proteins themselves, effectorproteins, e.g. phospholipase C, adenyl cyclase, and phosphodiesterase,and actator proteins, e.g. protein kinase A and protein kinase C (Simon,M. I. et al, Science, 1991, 252:802-8).

The membrane protein gene superfamily of G-protein coupled receptors hasbeen characterised as having seven putative transmembrane domains. Thedomains are believed to represent transmembrane α-helices connected byextracellular or cytoplasmic loops. G-protein coupled receptors includea wide range of biologically active receptors, such as hormone, viral,growth factor and neuro-receptors.

G-protein coupled receptors have been characterised as including theseseven conserved hydrophobic stretches of about 20 to 30 amino acids,connecting six divergent hydrophilic loops. The G-protein family ofcoupled receptors includes dopamine receptors which bind to neurolepticdrugs used for treating psychotic and neurological disorders. Otherexamples of members of this family include, but are not limited to,calcitonin, adrenergic, endothelin, cAMP, adenosine, muscarinic,acetylcholine, serotonin, histamine, thrombin, kinin, folliclestimulating hormone, opsins, endothelial differentiation gene-1,rhodopsins, odorant, and cytomegalovirus receptors.

Polypeptides and polynucleotides encoding the human 7-transmembraneG-protein coupled neuropeptide receptor, HFGAN72, have been identifiedand are disclosed in U.S. Ser. Nos. 08/846,704 and 08/846,705, both ofwhich were filed on Apr. 30, 1997, as well as in WO 96/34877.

Polypeptides and polynucleotides encoding polypeptides which are ligandsfor the HFGAN72 receptor are disclosed in U.S. Ser. No. 08/939,093 filedJul. 2, 1997, U.S. Ser. No. 08/820,519 filed Mar. 19, 1997 and U.S. Ser.No. 08/033,604 filed Dec. 17, 1996.

HFGAN72 receptors are found in the mammalian host and, thus, may beresponsible for many biological functions, including many pathologiesincluding, but not limited to, depression; anxiety; obsessive compulsivedisorder, affective neurosis/disorder; depressive neurosis/disorder,anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder;sexual dysfunction; psychosexual dysfunction; sex disorder; sexualdisorder; schizophrenia; manic depression; delerium; dementia; severemental retardation and dyskinesias such as Huntington's disease andGilles de la Tourett's syndrome; disturbed biological and circadianrhythms; feeding disorders, such as anorexia, bulimia, cachexia, andobesity; diabetes; asthma; cancer; Parkinson's disease; Cushing'ssyndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia;hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases;Froehlich's syndrome; adrenohypophysis disease; hypophysis disease;hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthhormone deficiency; dwarfism; gigantism; acromegaly; disturbedbiological and circadian rhythms; and sleep disturbances associated withsuch diseases as neurological disorders, neuropathic pain and restlessleg syndrome, heart and lung diseases, mental illness such as depressionor schizophrenia, and addictions; acute and congestive heart failue;hypotension; hypertension; urinary retention; osteoporosis; anginapectoris; myocardial infarction; ulcers; allergies; benign prostatichypertrophy; chronic renal failure; renal disease; impaired glucosetolerance; migraine; hyperalgesia; pain; enhanced or exaggeratedsensitivity to pain, such as hyperalgesia, causalgia and allodynia;acute pain; burn pain; atypical facial pain; neuropathic pain; backpain; complex regional pain syndromes I and II; arthritic pain; sportsinjury pain; pain related to infection, e.g. HIV, post-polio syndrome,and post-herpetic neuralgia; phantom limb pain; labour pain; cancerpain; post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; and tolerance to narcotics or withdrawal from narcotics;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lagsyndrome; and other neurodegenerative disorders, which includesnosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.

Experiments have shown that central administration of Lig 72A for theHFGAN72 receptor (Lig 72A is described in more detail below) stimulatedfood intake in freely-feeding rats during a 4 hour time period. Thisincrease was approximately four-fold over control rats receivingvehicle. These data suggest that Lig 72A may be an endogenous regulatorof appetite. Therefore, antagonists of its receptor may be useful in thetreatment of obesity and diabetes, see Cell, 1998, 92, 573-585.

There is a significant incidence of obesity in westernised societies.According to WHO definitions a mean of 35% of subjects in 39 studieswere overweight and a furter 22% clinically obese. It has been estimatedthat 5.7% of all healthcare costs in the USA are a consequence ofobesity. About 85% of Type 2 diabetics are obese, and diet and exerciseare of value in all diabetics. The incidence of diagnosed diabetes inwesternised countries is typically 5% and there are estimated to be anequal number undiagnosed. The incidence of both diseases is rising,demonstrating the inadequacy of current treatments which may be eitherineffective or have toxicity risks including cardiovascular effects.Treatment of diabetes with sulfonylureas or insulin can causehypoglycaemia, whilst metformin causes GI side-effects. No drugtreatment for Type 2 diabetes has been shown to reduce the long-termcomplications of the disease. Insulin sensitisers will be useful formany diabetics, however they do not have an anti-obesity effect.

Rat sleep/EEG studies have also shown that central administration ofLIG72A, an agonist of HFGAN72 receptors, causes a dose-related increasein arousal, largely at the expense of a reduction in paradoxical sleepand slow wave sleep 2, when administered at the onset of the normalsleep period. Therefore antagonists of its receptor may be useful in thetreatment of sleep disorders including insomnia

The present invention provides phenyl urea and phenyl thioureaderivatives which are non-peptide antagonists of the human HFGAN72receptor. In particular, these compounds are of potential use in thetreatment of obesity including obesity observed in Type 2(non-insulin-dependent) diabetes patients and/or sleep disorders.

Several phenyl urea derivatives are known in the literature, viz:

WO 93/18028 discloses the compoundN-1-isoquinolinyl-N′-(1-methyl-1H-indol-5-yl)urea;

DE 2928485 discloses the compoundsN-(3-chloro-4-trifluoromethylphenyl)-N′-4-quinolinylurea, andN-(3-chloro-4-trifluoromethylphenyl)-N′-(5-nitro-4-quinolinyl)urea;

DE 2801187 discloses the compoundN-(3,4,5-trimethoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea; and

U.S. Pat. No. 3,406,176 discloses the compoundsN-(4-methoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea, andN-(4-chlorophenyl)-N′-(7-chloro-4-quinolinyl)urea;

none of these documents suggest the use of phenyl urea derivatives asHFGAN72 receptor antagonists.

According to the present invention there is provided a compound offormula (I):

in which:

X and Y independently represent CH or nitrogen, provided that X and Y donot both represent CH;

Z represents oxygen or sulphur,

R¹ represents (C₁₋₆)alkyl, (C₂₋₆)alkenyl or (C₁₋₆)alkoxy, any of whichmay be optionally substituted; halogen, R⁷CO— or NR⁸R⁹CO—;

R², R³, R⁴, R⁵ and R⁶ independently represent (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkoxy or (C₁₋₆)alkylthio, any of which may beoptionally substituted; hydrogen, halogen, nitro, cyano, aryloxy,aryl(C₁₋₆)alkyloxy, aryl(C₁₋₆)alkyl, R⁷CO—, R⁷SO₂NH—, R⁷CON(R¹⁰)—,NR⁸R⁹—, NR⁸R⁹CO—, —COOR⁸ or heterocyclyl; provided that at least one ofR², R³, R⁴, R⁵ and R⁶ is other than hydrogen;

or an adjacent pair of R², R³, R⁴, R⁵ and R⁶ together with the carbonatoms to which they are attached form an optionally substitutedcarbocyclic or heterocyclic ring;

R⁷ is (C₁₋₆)alkyl or aryl;

R⁸ and R⁹ independently represent hydrogen, (C₁₋₆)alkyl, aryl oraryl(C₁₋₆)alyl;

R¹⁰ is hydrogen or (C₁₋₆)alkyl; and

n is 0, 1, 2, 3 or 4;

or a pharmaceutically acceptable salt thereof;

provided that the compound is not:

a) N-1-isoquinolinyl-N′-(1-methyl-1H-indol-5-yl)urea;

b) N-(3-chloro-4-trifuoromethylphenyl)-N′-4-quinolinylurea;

c) N-(3-chloro-4-trifluoromethylphenyl)-N′-(5-nitro-4-quinolinyl)urea;

d) N-(3,4,5-trimethoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea;

e) N-(4-methoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea; or

f) N-(4-chlorophenyl)-N′-(7-chloro-4-quinolinyl)urea

In formula (I) X preferably represents CH, Y preferably representsnitrogen and Z preferably represents oxygen.

When a halogen atom is present in the compound of formula (I) this maybe fluorine, chlorine, bromine or iodine.

n is preferably 0 or 1.

When Y is nitrogen and n is 1, the group R¹ is preferably in the 6- or8-position, particularly the 6-position.

R¹ is preferably halogen e.g. fluoro, or (C₁₋₆)alkoxy e.g. methoxy. R¹is most preferably fluoro.

When any one of R¹ to R⁶ comprise a (C₁₋₆)alkyl group, whether alone orforming part of a larger group, e.g. alkoxy or alkylthio, the alkylgroup may be straight chain or branched, it preferably contains 1 to 4carbon atoms and is most preferably methyl or ethyl.

When any one of R¹ to R⁶ comprise a (C₂₋₆)alkenyl group, whether aloneor forming part of a larger group, the alkenyl group may be straightchain or branched, it preferably contains 2 to 4 carbon atoms and ismost preferably allyl.

Suitable optional substituents for (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxy and (C₁₋₆)alkylthio groups include one or more substituentsselected from halogen e.g. fluoro, (C₁₋₄)alkoxy e.g. methoxy, hydroxy,carboxy and (C₁₋₆)alkyl esters thereof, amino, mono- ordi-(C1-6)alkylamino and cyano.

When used herein the term “aryl”, whether alone or forming part of alarger group, includes optionally substituted aryl groups such as phenyland naphthyl, preferably phenyl. The aryl group may contain up to 5,more preferably 1, 2 or 3 optional substituents. Examples of suitablesubstituents for aryl groups include halogen, (C₁₋₄)alkyl e.g. methyl,(C₁₋₄)haloalkyl e.g. trifluoromethyl, (C₁₋₄)alkoxy e.g. methoxy,(C₁₋₄)alkoxy(C₁₋₄)alkyl e.g. methoxymethyl, hydroxy, carboxy and(C₁₋₆)alkyl esters thereof, amino, nitro, arylsulphonyl e.g.p-toluenesulphonyl, and C₁₋₄ alkylsulphonyl e.g. methanesulphonyl.

When any one of R² to R⁶ represent heterocyclyl, this group ispreferably a 5- to 10-membered monocyclic or bicyclic ring, which may besaturated or unsaturated, for example containing 1, 2 or 3 heteroatomsselected from oxygen, nitrogen and sulphur; for example pyrrolidine,oxazole, morpholine, pyrimidine or phthalimide. A ring containing one ortwo nitrogen atoms is especially preferred. The heterocyclyl group maycontain up to 5, more preferably 1, 2 or 3 optional substituents.Examples of suitable substituents for heterocyclyl groups includehalogen, (C₁₋₄)alkyl e.g. methyl, (C₁₋₄)haloalkyl e.g. trifluoromethyl,(C₁₋₄)alkoxy e.g. methoxy, (C₁₋₄)alkoxy(C₁₋₄)alkyl e.g. methoxymethyl,hydroxy, carboxy, amino, nitro, arylsulphonyl e.g. p-toluenesulphonyl,and (C₁₋₄)alkylsulphonyl e.g. methanesulphonyl.

When an adjacent pair of R² to R⁶ together with the carbon atoms towhich they are attached form a carbocyclic or heterocyclic ring it ispreferably a 5- to 7-membered ring, which may be aromatic ornon-aromatic. Heterocyclic rings preferably contain 1, 2 or 3heteroatoms selected from oxygen, nitrogen and sulphur; for exampleoxazole, imidazole, thiophene, pyran, dioxan, pyrrole or pyrrolidine. Aring containing one nitrogen atom and one oxygen atom is preferred. Itis particularly preferred for the nitrogen to be attached directly tothe R⁴ position. A carbocyclic or heterocyclic ring formed by anadjacent pair of R² to R⁶ together with the carbon atoms to which theyare attached may be optionally substituted on carbon or nitrogen by oneor more substituents, e.g. up to 3 substituents. Examples of suitablesubstituents for the carbocyclic or heterocyclic ring include ═O,(C₁₋₄)alkyl e.g. methyl, aryl(C₁₋₄)alkyl e.g. benzyl or 3-phenylpropyl,aryl e.g. phenyl, (C₁₋₄)alkoxy, (C₁₋₄)alkoxy(C₁₋₄)alkyl e.g.methoxymethyl, hydroxy, hydroxy(C₁₋₄)alkyl e.g. hydroxyethyl, R^(a)CO₂—,R^(a)CO₂(C₁₋₄)alkyl e.g. carboethoxypropyl, cyano, cyano(C₁₋₄)alkyl e.g.3-cyanopropyl, R^(a)R^(b)N and R^(a)R^(b)N(C₁₋₄)alkyl; in which R^(a)and R^(b) are independently selected from hydrogen and (C₁₋₄)alkyl.

A preferred group of compounds are those in which R² to R⁶ independentlyrepresent hydrogen, halogen, (C₁₋₆)alkoxy e.g. methoxy, (C₁₋₆)alkylthioe.g. methylthio, or NR⁸R⁹ wherein R⁸ and R⁹ preferably represent(C₁₋₆)alkyl e.g. dimethylamino, and at least one of R² to R⁶ is otherthan hydrogen; or an adjacent pair of R² to R⁶ together with the carbonatoms to which they are attached form an optionally substituted 5- to7-membered heterocyclic ring, e.g. a 6 or 7-membered non-aromaticheterocyclic ring or a 5- or 6-membered aromatic heterocyclic ring.

A further preferred group of compounds are those in which R², R⁵ and R⁶represent hydrogen.

A further preferred group of compounds are those in which R², R⁴ and R⁶represent hydrogen.

A preferred group of compounds are those in which either R³ and R⁴, orR³ and R⁵ are other than hydrogen.

A group of compounds according to the invention which may be mentionedare the compounds of formula (Ia):

in which:

X and Y independently represent CH or nitrogen, provided that X and Y donot both represent CH;

Z represents oxygen or sulphur,

R¹ represents halogen or (C₁₋₆)alkoxy;

R³ and R⁴ independently represent hydrogen, halogen, nitro, cyano,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, aryloxy, CF₃O, (C₁₋₆)alkylthio, amino, mono-or di-(C₁₋₆)alkylamino, monoarylamino, mono(C₁₋₆)alkylarylarnino, R⁷CO—,R⁷SO₂NH—, R⁷CON(R¹⁰)—, NR⁸R⁹CO— or heterocyclyl;

or R³ and R⁴ together with the carbon atoms to which they are attachedform an optionally substituted carbocyclic or heterocyclic ring;

R⁷ is (C₁₋₆)alkyl or aryl;

R⁸ and R⁹ independently represent hydrogen, (C₁₋₆)alkyl, aryl or(C₁₋₆)alkylaryl;

R¹⁰ is hydrogen or (C₁₋₆)alkyl; and

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Another group of compounds according to the invention which may bementioned are the compounds of formula (Ib):

in which:

X and Y independently represent CH or nitrogen, provided that X and Y donot both represent CH;

Z represents oxygen or sulphur;

R¹ represents halogen or (C₁₋₆)alkoxy;

R³ and R⁴ independently halogen or (C₁₋₃)alkoxy or together with thecarbon atoms to which they are attached form an optionally substitutedheterocyclic ring; and

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable salts.

It will be appreciated that for use in medicine the salts of thecompounds of formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include for example acid addition salts formed withinorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric orphosphoric acid; and organic acids e.g. succinic, maleic, acetic,fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonicor naphthalenesulphonic acid. Other salts e.g. oxalates, may be used,for example in the isolation of compounds of formula (I) and areincluded within the scope of this invention. Also included within thescope of the invention are solvates and hydrates of compounds of formula(I).

The invention extends to all isomeric forms including stereoisomers andgeometric isomers of the compounds of formula (I) including enantiomersand mixtures thereof e.g. racemates. The different isomeric forms may beseparated or resolved one from the other by conventional methods, or anygiven isomer may be obtained by conventional synthetic methods or bystereospecific or asymmetric syntheses.

According to a further feature of the invention we provide a process forthe preparation of the compounds of formula (I) and salts thereof whichcomprises coupling a compound of formula (II);

with a compound of formula (III);

wherein A and B are appropriate functional groups to form the —NHCONH—or —NHCSNH— moiety when coupled; X, Y and n are as defined in formula(I); and R^(1′) to R^(6′) are R¹ to R⁶ as defined in formula (I) orgroups convertible thereto; and thereafter optionally and as necessaryand in any appropriate order, converting any R^(1′) to R^(6′) when otherthan R¹ to R⁶ respectively to R¹ to R⁶, and/or forming apharmaceutically acceptable salt thereof.

Suitable examples of groups A and B are:

(i) A is —CON₃ and B is —NH₂

(ii) A is —NH₂ and B is —NH₂

(iii) A is —CO₂H and B is —NH₂

(iv) A is —N═C═O and B is —NH₂

(v) A is —NH₂ and B is —N═C═O

(vi) A is —N═C═S and B is —NH₂

(vii) A is —NH₂ and B is —N═C═S

(viii) A is —NHCOL and B is —NH₂

(ix) A is —NH₂ and B is —NHCOL

(x) A is halogen and B is —NHCONH₂.

Wherein L is a leaving group such as chloro or bromo, imidazole orphenoxy or phenylthio optionally substituted for example with halogen,for example chlorine.

When A and B are both NH₂, the reaction is generally effected in thepresence of a urea coupling agent such as carbonyldiimidazole.

When A is —CO₂H and B is —NH₂ the reaction is generally effected in thepresence of an agent such as diphenylphosphoryl azide and in thepresence of a base such as triethylamine.

When A is —NH₂, —N═C═O or —N═C═S and B is —NH₂, or when A is —NH₂ and Bis —N═C═O or —N═C═S the reaction is suitably carried out in an inertsolvent for example dimethylformamide or dichloromethane and/or tolueneat ambient or elevated temperature, preferably ambient.

When A is —CON₃ or —CO₂H and B is —NH₂ the reaction is suitably carriedout in an inert solvent for example toluene or dimethylformamide atelevated temperature.

Where A is —NHCOL and B is —NH₂ or when A is —NH₂ and B is —NHCOL, thereaction is suitably carried out in an inert solvent such asdichloromethane at ambient temperature optionally in the presence of abase, such as triethylamine or in dimethylformamide at ambient orelevated temperature.

When A is halogen and B is —NHCONH₂ the reaction is suitably carried outin an inert solvent such as toluene at elevated temperature, optionallyin the presence of base.

Suitable examples of compounds having groups R^(1′) to R^(6′) which areconvertible to R¹ to R⁶ respectively include compounds where an adjacentpair of R^(2′) to R^(6′) together with the carbon atoms to which theyare attached represent a fused pyrrole ring which is unsubstituted onnitrogen, where treatment with a base, e.g. sodium hydride, and reactionwith an electrophile, e.g. methyl iodide, benzyl chloride orbenzenesulfonyl chloride, affords the corresponding substituent on thepyrrole nitrogen.

Compounds of formula (II) where A is —NH₂ are known compounds or can beprepared analogously to known compounds.

Compounds of formula (II) where A is —N═C═O may be prepared by treatinga compound of formula (II) in which:

(i) A is amino, with phosgene or a phosgene equivalent, in the presenceof excess base or an inert solvent.

(ii) A is acylazide (i.e. —CON₃), via the nitrene, by thermalrearrangement using conventional conditions (ref. L. S. Trifonov et al,Helv. Chim. Acta, 1987, 70, 262).

(iii) A is —CONH₂, via the nitrene intermediate using conventionalconditions.

Compounds of formula (II) where A is —N═C═S are known compounds or canbe prepared analogously to known compounds.

Compounds of formula (II) where A is —NHCOL may be prepared by reactinga compound of formula (II) in which A is —NH₂ with phosgene or aphosgene equivalent, in an inert solvent, at low temperature, ifnecessary in the presence of a base such as triethylamine.

Compounds of formula (II) in which A is halogen are known compounds orcan be prepared analogously to known compounds.

Compounds of formula (III) where B is —NH₂ are known compounds or can beprepared analogously to known compounds.

Compounds of formula (III) where B is —N═C═O may be prepared by treatinga compound of formula (III) in which:

(i) B is amino, with phosgene or a phosgene equivalent, in the presenceof excess base or an inert solvent.

(ii) B is acylazide (i.e. —CON₃), via the nitrene, by thermalrearrangement using conventional conditions (ref. L. S. Trifonov et al,Helv. Chim. Acta, 1987, 70, 262).

(iii) B is —CONH₂, via the nitrene intermediate using conventionalconditions.

Compounds of formula (UT) where B is —N═C═S are known compounds or canbe prepared analogously to known compounds.

Compounds of formula (III) where B is —NHCOL may be prepared by reactinga compound of formula (III) in which B is —NH₂ with phosgene or aphosgene equivalent, in an inert solvent, at low temperature, ifnecessary in the presence of a base such as triethylamine. Examples ofphosgene equivalents include triphosgene, carbonyldiimidazole, phenylchloroformate and phenyl chlorothioformate.

Compounds of formula (III) where B is —NHCONH₂ can be prepared from thecorresponding precursor where B is —NH₂ by reaction with an isocyanateunder conventional conditions.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds of formula (I). Libraries ofcompounds of formula (I) may be prepared by a combinatorial ‘split andmix’ approach or by multiple parallel synthesis using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I) orpharmaceutically acceptable salts thereof.

Novel intermediates of formulae (II) and (III) are also part of thisinvention.

According to a further feature of the invention we provide a compound offormula (II):

wherein A is —CON₃, —NH₂, —CO₂H, —N═C═O, —N═C═S, —NHCOL or halogen, L isa leaving group, X and Y are as defined in formula (I), n is 1, 2, 3 or4, and R^(1′) is R¹ as defined in formula (I) or a group convertiblethereto.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

As indicated above the compounds of formula (I) and theirpharmaceutically acceptable salts, including those compounds where X andY both represent CH, and without provisos a)-f), are useful for thetreatment of diseases or disorders where an antagonist of the humanHFGAN72 receptor is required especially feeding disorders, such asobesity and diabetes; prolactinoma; hypoprolactinemia, hypothalamicdisorders of growth hormone deficiency; idiopathic growth hormonedeficiency; Cushings syndrome/disease; hypothalamic-adrenal dysfunction;dwarfism; sleep disorders; sleep apnea; narcolepsy; insomnia;parasomnia; jet-lag syndrome; and sleep disturbances associated withsuch diseases as neurological disorders, neuropathic pain, restless legsyndrome, heart and lung diseases, mental illness such as depression orschizophrenia, and addictions; sexual dysfunction; psychosexualdysfunction; sex disorder; sexual disorder; bulimia; andhypopituitarism.

The compounds of formula (I) and their pharmaceutically acceptablesalts, including those compounds in which X and Y both represent CH, andwithout provisos a)-f), are particularly useful for the treatment ofobesity, including obesity associated with Type 2 diabetes, and sleepdisorders.

Other diseases or disorders which may be treated in accordance with theinvention include disturbed biological and circadian rhythms;adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma;adrenohypophysis hypofunction; functional or psychogenic amenorrhea;adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhancedor exaggerated sensitivity to pain such as hyperalgesia, causalgia andallodynia; acute pain; burn pain; atypical facial pain; neuropathicpain; back pain; complex regional pain syndromes I and II; arthriticpain; sports injury pain; pain related to infection, e.g. HIV,post-polio syndrome and post-herpetic neuralgia; phantom limb pain;labour pain; cancer pain; post-chemotherapy pain; post-stroke pain;post-operative pain; neuralgia; and tolerance to narcotics or withdrawalfrom narcotics.

The present invention also provides a method of treating or preventingdiseases or disorders where an antagonist of the human HFGAN72 receptoris required, which comprises administering to a subject in need thereofan effective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, without the proviso that X and Y do not bothrepresent CH and without provisos a)-f).

The present invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, without the proviso that X andY do not both represent CH and without provisos a)-f), for use in thetreatment or prophylaxis of disease or disorders where an antagonist ofthe human HFGAN72 receptor is required.

The present invention also provides the use of a compound of formula (I)or a pharmaceutically acceptable salt thereof, without the proviso thatX and Y do not both represent CH and without provisos a)-f), in themanufacture of a medicament for the treatment or prophylaxis of diseasesor disorders where an antagonist of the human HFGAN72 receptor isrequired.

For use in medicine, the compounds of the present invention are usuallyadministered as a pharmaceutical composition. The present invention alsoprovides a pharmaceutical composition comprising a compound of formula(I) or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The compounds of formula (I) and their pharmaceutically acceptablesalts, including those compounds in which X and Y both represent CH andwithout provisos a)-f), may be administered by any convenient method,for example by oral, parenteral, buccal, sublingual, nasal, rectal ortransdermal administration and the pharmaceutical compositions adaptedaccordingly.

The compounds of formula (I) and their pharmaceutically acceptablesalts, including those compounds in which X and Y both represent CH andwithout provisos a)-f), which are active when given orally can beformulated as liquids or solids, for example syrups, suspensions oremulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or physiologically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring and/or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or physiologically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochlorohydrocarbon orhydrofluorocarbon. The aerosol dosage forms can also take the form of apump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

The dose of the compound of formula (I) or a pharmaceutically acceptablesalt thereof, including those compounds in which X and Y both representCH and without provisos a)-f), used in the treatment or prophylaxis ofthe abovementioned disorders or diseases will vary in the usual way withthe particular disorder or disease being treated, the weight of thesubject and other similar factors. However as a general rule suitableunit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, forexample 0.2 to 5 mg; such unit doses may be administered more than oncea day for example two or three times a day, so that the total dailydosage is in the range of about 0.01 to 100 mg/kg; and such therapy mayextend for a number of weeks or months. In the case of physiologicallyacceptable salts the above figures are calculated as the parent compoundof formula (I), including those compounds in which X and Y bothrepresent CH and without provisos a)-f).

No toxicological effects are indicated/expected when a compound offormula (I), including those compounds in which X and Y both representCH and without provisos a)-f), is administered in the above mentioneddosage range.

The human HFGAN72 receptor ligand 72A referred to above has the aminoacid sequence:

Gln Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys 1              5                   10 Ser Cys Arg Leu Tyr Glu Leu LeuHis Gly Ala Gly Asn His Ala Ala          15                10 10 20 AsnHis Ala Ala Gly Ile Leu Thr Leu-NH₂ 25                  30

The HFGAN72 receptor ligand referred to above can be employed in aprocess for screening for compounds (antagonists) which inhibit theligand's activation of the HFGAN72 receptor.

In general, such screening procedures involve providing appropriatecells which express the HFGAN72 receptor on the surface thereof. Suchcells include cells from mammals, yeast, Drosophila or E. coli. Inparticular, a polynucleotide encoding the HFGAN72 receptor is employedto transfect cells to thereby express the receptor. The expressedreceptor is then contacted with a test compound and an HFGAN72 receptorligand to observe inhibition of a functional response.

One such screening procedure involves the use of melanophores which aretransfected to express the HFGAN72 receptor. Such a screening techniqueis described in WO 92/01810.

Another such screening technique involves introducing RNA encoding theHFGAN72 receptor into Xenopus oocytes to transiently express thereceptor. The receptor oocytes may then be contacted with a receptorligand and a compound to be screened, followed by detection ofinhibition of a signal in the case of screening for compounds which arethought to inhibit activation of the receptor by the ligand.

Another method involves screening for compounds which inhibit activationof the receptor by determining inhibition of binding of a labelledHFGAN72 receptor ligand to cells which have the receptor on the surfacethereof. Such a method involves transfecting a eukaryotic cell with DNAencoding the HFGAN72 receptor such that the cell expresses the receptoron its surface and contacting the cell or cell membrane preparation witha compound in the presence of a labelled form of an HFGAN72 receptorligand. The ligand can be labelled, e.g. by radioactivity. The amount oflabelled ligand bound to the receptors is measured, e.g. by measuringradioactivity of the receptors. If the compound binds to the receptor asdetermined by a reduction of labelled ligand which binds to thereceptors, the binding of labelled ligand to the receptor is inhibited.

Yet another screening technique involves the use of FLIPR equipment forhigh throughput screening of test compounds that inhibit mobilisation ofintracellular calcium ions, or other ions, by affecting the interactionof an HFGAN72 receptor ligand with the HFGAN72 receptor. The ligand usedin the screening method described below to determine the antagonistactivity of compounds according to the invention is Lig 72A which hasthe amino acid sequence shown above.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Examples illustrate the preparation of pharmacologicallyactive compounds of the invention. The following Descriptions D1-D33illustrate the preparation of intermediates to compounds of the presentinvention.

In the Examples ¹H NMR's were measured at 250 MHz in d₆-DMSO unlessotherwise stated. All hydrochloride salts unless otherwise stated wereprepared by dissolving/suspending the free-base in methanol and treatingwith an excess of ethereal HCl (1M).

Descriptions

D1 Methyl quinoline-4-carboxylate

Thionyl chloride (4.5 ml) was added dropwise, under argon to a cooled,stirring slurry of 4-quinolinecarboxylic acid (5.32 g) in methanol (120ml) maintaining an internal temperature of 0 to −5° C. Once addition wascomplete the reaction mixture was heated at reflux for 16 h. Aftercooling to ambient temperature the volatiles were removed at reducedpressure and the residue partitioned between saturated aqueous sodiumbicarbonate and diethyl ether. The organic phase was washed with brine,dried (Na₂SO₄) and the solvent removed at reduced pressure to give thetitle compound as a pale yellow oil (4.82 g).

¹H NMR (CDCl₃) δ: 4.05 (3H, s), 7.66 (1H, m), 7.77 (1H, m), 7.91 (1H, d,J 4 Hz), 8.18 (1H, dd, J 1+9 Hz), 8.78 (1H, dd, J 1+9 Hz), 9.02 (1H, d,J 4 Hz).

m/z (API⁺): 188 (MH⁺).

Alternatively the title ester can be prepared, using standard chemistry,in 42% yield from 4-quinolinecarboxylic acid, methanol and c.H₂SO₄.

D2 Quinoline-4-carboxylic acid hydrazide

D1 (1.35 g) in ethanol (50 ml) was treated with hydrazine hydrate (2.0ml, 98%, excess) and the mixture heated at reflux under argon for 14 h.The reaction mixture was cooled to ambient temperature and the volatilesremoved at reduced pressure. Trituration of the residue with diethylether gave the title compound as a yellow solid (1.32 g).

¹H NMR δ: 4.46 (2H, bs), 7.33 (1H, d, J 4 Hz), 7.48 (1H, m), 7.63 (1H,m), 7.90 (1H, d, J 8 Hz), 7.99 (1H, d, J 8 Hz), 8.78 (1H, d, J 4 Hz),9.75 (1H, bs).

m/z (API⁺): 188 (MH⁺).

D3 Quinoline-4-carbonyl azide

A cooled slurry of D2 (1.34 g) in water (5.00 ml) was treated drop-wisewith c.HCl (1.44 ml) maintaining an internal temperature of 0 to 5° C. Acooled solution of sodium nitrite (1.08 g) in water (1.44 ml) was addeddropwise over 15 min maintaining the same internal temperature. Thesolution was then neutralised with saturated aqueous sodium bicarbonate.The title compound was collected by filtration as a white solid whichwas washed with water then dried at reduced pressure at ambienttemperature (1.00 g).

¹H NMR (CDCl₃) δ: 7.72 (1H, m), 7.82 (1H, m), 7.95 (1H, d, J 4 Hz), 8.19(H, d, J 8 Hz), 8.91 (1H, d, J 8 Hz), 9.05 (1H, d, J 4 Hz).

D4 4-Aminoquinoline

Method 1

A mixture of 4-nitroquinoline-N-oxide (0.700 g) and 10% palladium oncharcoal (0.700 g) was hydrogenated at atmospheric pressure for 16 h.The catalyst was removed by filtration and the methanol removed atreduced pressure. As ¹H NMR indicated that starting material stillremained the hydrogenation was repeated with a further batch of catalyst(0.500 g) and worked up as described previously. The resulting residuewas recrystallised (methanol/toluene/hexane) to give the title amine asa solid (0.350 g).

¹H NMR δ: 6.55 (1H, d, J 5 Hz), 6.77 (2H, s), 7.37 (1H, m), 7.60 (1H,m), 7.74 (1H, d, J 8 Hz), 8.15 (1H, d, J 8 Hz), 8.27 (1H, d, J 5 Hz).

Method 2

a) Quinolin-4-yl carbamic acid tert butyl ester

Quinoline-4-carboxylic acid (13.0 g) and diphenylphosporyl azide (16.2ml) were combined in tert butanol (180 ml) containing triethylamine (11ml). The mixture was boiled for 24 h. Solvent was removed at reducedpressure and the residue partitioned between water and ethyl acetate.The aqueous phase was extracted with ethyl acetate (×4). The combinedorganinc extracts were washed with saturated brine, dried and solventremoved at reduced pressure. The residue was dissolved in methanol/ethylacetate filtered and the filtrate evaporated at reduced pressure. Theresidue was column chromatographed (silica gel, ethyl acetate eluant) togive the title compound (16.8 g).

¹H NMR δ: 1.54 (9H, s), 7.53-7.59 (1H, m), 7.71 -7.77 (1H, m), 7.92 (1H,d, J 5.2 Hz), 7.96 (1H, d, J 8.4 Hz), 8.37 (1H, d, J 8.4 Hz), 8.75 (1H,d, J 5.2 Hz), 9.82 (1H, s).

b) 4-Aminoquinoline

A solution of quinolin-4-yl carbamic acid tert butyl ester (16.8 g) in5N HCl (200 ml) was boiled for 5 h. The reaction mixture was dilutedwith water made basic with sodium hydroxide and washed withdichloromethane. The aqueous phase was separated and evaporated todryness at reduced pressure. The residue was dissolved in propan-1-ol,insoluble material separated by filtration and the filtrate evaporatedto dryness. The residue was dissolved in dichloromethane/ethyl acetate,filtered to remove insoluble inorganic salts and solvent removed atreduced pressure to give 4-aminoquinoline (8.7 g).

D5 Synthesis of 5-nitro-1-substituted-(1H)-indoles

5-Nitroindole and potassium or caesium carbonate (1.5 eq.) were stirredtogether for 15 min. in dimethylformamide. The alkyl halide (1.1 eq.)was added and the reaction mixture stirred until tic indicateddisappearance of 5-nitroindole. The mixture was poured into water andthe precipitated product separated by filtration.

m/z Product Product name Alkyl halide Base (M + H) Yield D5(A)1-ethyl-5-nitro- bromoethane K₂CO₃ 191  84% (1H)-indole D5(B)5-nitro-1-(3- 3-phenylpropyl K₂CO₃ 281  82% phenylpropyl)- bromide(1H)-indole D5(C) 1-benzyl-5- Benzyl bromide Cs₂CO₃ 253  87% nitro-(1H)-indole D5(D) 4-(5-Nitroin- ethyl 4- Cs₂CO₃ 277  86% dol-1-yl)butyricbromobutyrate acid ethyl ester D5(E) 4-(5-Nitroin- 3-cyanopropyl Cs₂CO₃230 100% dol-1-yl)buty- bromide ronitrile

D6 Synthesis of 5-amino-1-substituted-(1H)-indoles

The appropriate 5-nitro-1-substituted-(1H)-indole (1 g) and 10%palladium/charcoal (0.5 g) in ethanol (120 ml) was treated with ammoniumformate (5 eq.) in one portion and the mixture stirred for 16 h. Themixture was filtered through a celite pad and solvent removed at reducedpressure. The residue was partitioned between water and ethyl acetate,washed with water and sodium bicarbonate to give, after drying (Na₂SO₄)and removal of solvent at reduced pressure, the required compound.

Starting m/z Material Product Product name (M+ H) Yield D5(A) D6(A)5-amino-1-ethyl-(1H)- 161 56% indole D5(B) D6(B) 5-amino-1-(3- 251 31%phenylpropyl)-(1H)-indole D5(C) D6(C) 5-amino-1-benzyl-(1H)- 223 100% indole D5(D) D6(D) 4-(5-aminoindol-1- 247 55% yl)butyric acid ethylester D5(E) D6(E) 4-(5-aminoindol-1- 200 80% yl)butyronitrile

D7 Synthesis of 5-nitro-1-substituted-(1H)-indolines

5-Nitroindoline was dissolved in dimethylformamide (4 ml/mmol), sodiumhydride added (1.5 eq., 60% suspension in oil) and the mixture stirredfor 1 h. The appropriate alkylating agent (2 eq.) was added and themixture stirred until tlc showed complete reaction. The mixture waspoured into water and the precipitated product collected by filtration.

m/z Product Product name Alkyl Halide Time (M + H) Yield D7(A)1-methyl-5-nitro- iodomethane 6 h 179 83% (1H)-indoline

D8 Synthesis of 5-amino-1-substituted-(1H)-indolines

The appropriate 5-nitro-1-substituted-(1H)-indoline was stirred in amixture of methanol/water and sodium dithionite (4.5 eq.) and sodiumhydrogen carbonate (4.5 eq.) added. The mixture was stirred at roomtemperature overnight and methanol removed at reduced pressure. Theaqueous residue was extracted with ethyl acetate (2×). The combinedorganic phases were washed with water, dried (Na₂SO₄), and solventremoved at reduced pressure to give the target5-amino-1-substituted-(1H)-indoline.

Starting material Product Product Name m/z (M + H) Yield D7(A) D8(A)5-amino-1-methyl-1H- 149 56% indoline

D9 2-[(2-Bromo-5-methoxyphenylamino)methylene]malonic acid diethyl ester

A mixture of 3-amino-4-bromoanisole (1.40 g) and diethylethoxymethylene-malonate (1.4 ml) was heated at 100° C. for 4 h. Thereaction mixture was cooled and ethanol removed at reduced pressure togive the title compound as a waxy brown solid (2.55 g).

¹H NMR (CDCl₃) δ: 1.34 (3H, t), 1.39 (3H, t), 3.83 (3H, s), 4.26 (2H,q), 4.35 (2H, q), 6.58 (1H, dd, J 2.7+8.8 Hz), 6.80 (1H, d, J 2.7 Hz),7.46 (1H, d, J 8.8 Hz), 8.46 (1H, d, J 13 Hz), 11.20 (1H, d, J 13 Hz).

D10 8-Bromo-4-chloro-5-methoxyquinoline-3-carboxylic acid ethyl ester

D9 (2.55 g) in phosphoryl chloride (10 ml) was boiled for 16 h. Excessphosphoryl chloride was removed at reduced pressure, the residuedissolved in dichloromethane and washed with aqueous sodium hydrogencarbonate. The organic phase was dried (Na₂SO₄), solvent removed atreduced pressure and the residue triturated with hexane/diethyl ether togive the title compound (2.05 g) as a beige solid.

¹H NMR (CDCl₃) δ: 1.44 (3H, t), 3.99 (3H, s), 4.49 (2H, q), 6.89 (1H,d), 8.04 (1H, d), 9.06 (1H, s).

D11 8-Bromo-4-(4-methoxybenzyl)amino-5-methoxyquinoline-3-carboxylicacid ethyl ester

A mixture of D10 (2.1 g) and 4-methoxybenzylamine (1.57 ml) in xylene(40 ml) was boiled for 4 h. The mixture was cooled to room temperature,filtered and the residue washed with xylene. The combined filtrate andwashings were washed with sodium bicarbonate and brine, dried (Na₂SO₄)and solvent removed at reduced pressure to give after chromatography(silica gel, ethyl acetate/hexane 20%-50%) the title compound (2.13 g)as a waxy yellow solid.

¹H NMR (CDCl₃) δ: 1.40 (3H, t), 3.81 (3H, s), 3.84 (3H, s), 4.21 (2H,d), 4.40 (2H, q), 6.67 (1H, d), 6.87 (2H, d), 7.21 (2H, d), 7.86 (1H,d), 8.64 (1H, bs), 9.00 (1H, s).

D12 4-(4-Methoxybenzyl)amino-5-methoxyquinoline-3-carboxylic acid ethylester

A slurry of palladium on charcoal (10%, 0.5 g) in ethanol (8 ml) wasadded to D11 (2.0 g) in ethanol (90 ml). Ammonium formate (1.88 g) wasadded and the mixture stirred at room temperature for 6 h, filtered andsolvent removed at reduced pressure. The residue was dissolved in ethylacetate, washed with aqueous sodium bicarbonate and brine, dried(Na₂SO₄) and solvent removed at reduced pressure to give the titlecompound (1.50 g) as a yellow gum.

¹H NMR (CDCl₃) δ: 1.41 (3H, t), 3.81 (3H, s), 3.84 (3H, s), 4.21 (2H,d), 4.40 (2H, q), 6.79 (1H, dd), 6.89 (2H, d), 7.22 (2H, d), 7.48-7.59(2H, m), 8.59 (1H, bs), 8.87 (1H, s).

D13 4-(4-Methoxybenzyl)amino-5-methoxyquinoline-3-carboxylic acid

D12 (1.50 g) was added to a solution of potassium hydroxide (0.35 g) inaqueous ethanol (55 ml, 10:1) and the mixture boiled for 16 h.Additional potassium hydroxide (0.1 g) was added and heating continuedfor a further 6 h. Ethanol was removed at reduced pressure. The residuewas treated with water (75 ml) and washed with ethyl acetate. Theaqueous phase was acidified with 5N HCl, sodium hydrogen carbonate addedand finally acetic acid. The gel generated was separated by filtrationand the residue dried in vacuo to give the title compound (1.42 g) as abrown solid.

m/z (API⁺): 295 (MH⁺).

D14 4-(4-Methoxybenzyl)amino-5-methoxyquinoline

D13 (1.42 g) was boiled in diphenyl ether (10 ml) for 15 min. The cooledsolution was poured into hexane with vigorous stirring and theprecipitated product collected by filtration to give the title compound(1.15 g).

¹H NMR (CDCl₃) δ: 3.82 (3H; s), 3.94 (3H, s), 4.41 (2H, d), 6.29 (1H,d), 6.74 (1H, d), 6.91 (2H, d), 7.30 (2H, d), 7.47 (1H, t), 7.57 (1H,d), 7.97 (1H, bs), 8.39 (1H, d).

D15 4-Amino-5-methoxyquinoline

D14 (1.14 g) was cooled (ice bath) and trifluoroacetic acid (10 ml)added, followed by anisole (0.81 ml) and c.H₂SO₄ (1 drop). The mixturewas stirred at room temperature for 4 h, poured onto ice and neutralisedwith potassium carbonate. The aqueous phase was extracted withdichloromethane (4×30 ml), the combined organic extracts washed withwater, dried (Na₂SO₄) and solvent removed at reduced pressure. Theresidue was column chromatographed to give the title compound (0.25 g)as a pale brown solid.

¹H NMR (CDCl₃) δ: 3.98 (3H, s), 5.95 (2H, bs), 6.39 (1H, d), 6.71 (1H,dd), 7.43-7.56 (2H, m), 8.36 (1H, d).

D16 8-Bromoquinoline-4-carboxylic acid hydrazide

The title compound (0.95 g) as a yellow solid was obtained according tothe method of D2 from 8-bromoquinolin-4-carboxylic acid ethyl ester(1.04 g, E. R. Buchman et al., J. Amer. Chem. Soc., 1946, 68, 2692) inethanol (40 ml) and hydrazine hydrate (1.2 ml, 98%), the mixture wasboiled for 6 h, additional hydrazine hydrate (0.5 ml) added and heatingcontinued for a further 16 h.

m/z (API⁺): 267 (MH⁺).

D17 8-Bromoquinoline-4-carboxylic acid azide

From D16 (0.92 g) in water (8 ml), c.HCl (0.72 ml) and sodium nitrite(0.52 g) in water (0.8 ml), the title compound (0.85 g) was obtainedaccording to the method of D3.

¹H NMR δ: 7.69 (1H, t), 8.07 (1H, d), 8.29 (1H, d), 8.76 (1H, d), 9.21(1H, d).

D18 2-(2-Methoxyphenylamino)methylenemalonic acid diethyl ester

From 2-anisidine (12.3 g) and diethyl ethoxymethylenemalonate (21.6 g)the title compound (29 g) was obtained as a waxy brown solid accordingto the method of D9.

¹H NMR (CDCl₃) δ: 1.33 (3H, t), 1.37 (3H, t), 3.93 (3H, s), 4.24 (2H,q), 4.33 (2H, q), 6.90-7.01 (2H, m), 7.09 (1H, t), 7.24 (1H, d), 8.56(1H, d), 11.08 (1H, d).

D19 4-Chloro-8-methoxyquinoline-3-carboxylic acid ethyl ester

D18 (10 g) in phosphoryl chloride (15 ml) was boiled for 2 h. Excessphosphoryl chloride was removed at reduced pressure and the residueazeotroped with toluene (2×50 ml). The residue was dissolved in ethylacetate, washed with aqueous sodium hydrogen carbonate, the organicphase dried (Na₂SO₄) and solvent removed at reduced pressure to give thetitle compound (7.96 g) as a brown oil.

¹H NMR (CDCl₃) δ: 1.47 (3H, t), 4.11 (3H, s), 4.49 (2H, q), 7.20 (1H,d), 7.63 (1H, t), 7.97 (1H, d), 9.18 (1H, s).

D20 4-(4-Methoxybenzyl)amino-8-methoxyquinoline-3-carboxylic acid ethylester

From D19 (11.97 g), 4-methoxybenzylamine (11.8 ml) in xylene (100 ml),boiling for 12 h and washing with dichloromethane, the title compound(15.0 g) was obtained as a waxy yellow solid according to the method ofD11.

m/z (API⁺): 367 (MH⁺).

D21 4-(4-Methoxybenzyl)amino-8-methoxyquinoline-3-carboxylic acid

D20 (14.68 g) was boiled in a mixture of 2N sodium hydroxide and ethanol(250 ml, 2:3) for 2 h. The reaction mixture was cooled and acetic acid(15 ml) added. Ethanol (100 ml) was removed and the precipitated titlecompound collected by filtration.

m/z (API⁺): 339 (MH⁺).

D22 4-(4-Methoxybenzyl)amino-8-methoxyquinoline

From D21 (1.0 g) and diphenyl ether (5 ml) the title compound (0.78 g)was obtained as a brown solid according to the method of D14.

m/z (API⁺): 295 (MH⁺).

D23 4-Amino-8-methoxyquinoline

From D22 (0.73 g) and anisole (0.52 ml) the title compound (0.40 g) wasobtained as a pale brown solid according to the method of D15.

¹H NMR (CDCl₃) δ: 4.06 (3H, s), 4.69 (2H, bs), 6.63 (1H, d), 7.01 (1H,d), 7.29-7.41 (2H, m), 8.55 (1H, d).

D24 7-Bromoquinoline-4-carboxylic acid hydrazide

The title compound (0.295 g) was obtained as an off-white solid aftertrituration with diethyl ether from 7-bromoquinoline-4-carboxylic acidmethyl ester (0.50 g) and hydrazine hydrate (0.6 ml) according to themethod of D2.

m/z (API⁺): 266, 268 (MH⁺).

D25 7-Bromoquinoline-4-carboxylic acid azide

From D24 (0.254 g) in water (5 ml), c.HCl (0.20 ml) and sodium nitrite(0.143 g) in water (1.0 ml), the title compound (0.229 g) was obtainedaccording to the method of D3.

¹H NMR δ: 7.96 (1H, dd), 8.03 (1H, d), 8.39 (1H, dd), 8.72 (1H, d), 9.14(1H, d).

D26 6-Bromoquinoline-4-carboxylic acid hydrazide

The title compound (0.437 g) was obtained as an off-white solid aftertrituration with diethyl ether from 6-bromoquinoline-4-carboxylic acidethyl ester (0.50 g) and hydrazine hydrate (0.6 ml) according to themethod of D2.

m/z (API⁺): 266, 268 (MH⁺).

D27 6-Bromoquinoline-4-carboxylic acid azide

From D26 (0.405 g) in water (5 ml), c.HCl (0.30 ml) and sodium nitrite(0.228 g) in water (1.0 ml), the title compound (0.375 g) was obtainedaccording to the method of D3 as a cream solid.

¹H NMR δ: 7.92-8.12 (3H, m), 8.99 (1H, d), 9.14 (1H, d).

D28 8-Acetyl-4-quinoline carboxylic acid methyl ester

8-Bromo4-quinoline carboxylic acid methyl ester, D16 (E. R. Buchman etal., J. Amer. Chem. Soc., 1946, 68, 2692), (0.712 g),(1-ethoxyvinyl)tributyltin (1.60 g) andtetrakis(triphenylphosphine)palladium (O) in 1,4-dioxane (50 ml) wereheated at reflux for 16 h. The reaction mixture was cooled to ambienttemperature, HCl (5M, 1 ml) and water (15 ml) added and the resultingmixture stirred for 3 h. The solvent was removed at reduced pressure,the residue suspended in EtOAc and the solid removed by filtration. Theorganic phase was washed with saturated sodium bicarbonate, dried(Na₂SO₄), removal of the solvent under reduced pressure gave a dark oilwhich was chromatographed (silica gel, hexane diethyl ether) to give thetitle compound (0.500 g).

¹H NMR (CDCl₃) δ: 2.90 (3H, s), 4.06 (3H, s), 7.70 (1H, dd, J 8+9 Hz),7.94 (2H, m), 8.90 (1H, dd, J 1+9 Hz), 9.07 (1H, d, J 4 Hz).

m/z (API⁺): 230 (MH⁺).

D29 8-Acetyl-4-quinolinecarboxylic acid

D28 (0.490 g) in methanol (5 ml) was stirred with NaOH (2M, 3 ml) underargon for 2.5 h. After addition of c.HCl to pH1, solvent was removed atreduced pressure. The residue was triturated with ethanol andpropan-1-ol, the mixture filtered to remove the in organics and thesolvent removed under reduced pressure to give the title compound as apale orange solid (0.360 g).

¹H NMR δ: 2.78 (3H, s), 7.81 (1H, dd, J 8 Hz), 7.93 (1H, d, J 8 Hz),8.03 (1H, d, J 4 Hz), 8.09 (1H, d, J 8 Hz), 9.14 (1H, d, J 4 Hz).

D30 Benzoxazole-6-carboxylic acid

4-Amino-3-hydroxybenzoic acid (2.200 g) and formic acid (20 ml) wereheated at 117° C. for 4 h. The reaction mixture was cooled to ambienttemperature and the precipitated solid collected by filtration, washedwith diethyl ether and dried at reduced pressure. The solid (0.580 g)was heated at reflux with zinc chloride (2.00 g) and c.H₂SO₄ (2 drops)in xylene (150 ml) under a Dean and Stark for 16 h. On cooling, waterwas added and the brown solid collected by filtration and washed withwater. The resulting solid was washed with methanol and the solventremoved from the filtrate under reduced pressure to give the titlecompound as a dark brown solid (0.349 g).

¹H NMR δ: 7.90 (1H, d, J 8 Hz), 8.02 (1H, dd, J 1+8 Hz), 8.29 (1H, d, J2 Hz), 8.94 (1H, s).

D31 Benzoxazole-5-carboxylic acid

From 3-amino-2-hydroxybenzoic acid (1.049 g) the title compound (0.800g) was prepared according to the method of D30.

¹H NMR δ: 7.89 (1H, d, J 8 Hz), 8.07 (1H, dd, J 2+8 Hz), 8.33 (1H, d, J2 Hz), 8.89 (1H, s).

D32 6-Fluoroquinoline-2,4-dicarboxylic acid

5-Fluoroisatin (9.74 g) was added to a hot solution of 33% potassiumhydroxide (29.1 g in 85 ml water). Pyruvic acid (9.25 g) was added, themixture stirred at room temperature for 1 h and boiled for 1 h. Themixture was cooled to room temperature and acidified with c.HCl. Afterrefridgerating overnight, the precipitated material was collected byfiltration and dried in vacuo at 50° C. to give the title compound (14.5g).

¹H NMR δ: 7.85-7.93 (1H, m), (1H, dd, J 5.9+9.3 Hz), 8.59 (1H, dd, J5.7+9.3 Hz), 13.90 (2H, bs).

m/z (API⁺): 236 (MH⁺).

D33 6-Fluoroquinoline-4-carboxylic acid

6-Fluoroquinoline-2,4-dicarboxylic acid (14.2 g) in nitrobenzene (50 ml)was boiled for 30 min in a reaction vessel equipped with a Dean-Starkapparatus. The mixture was cooled to room temperature and theprecipitated material triturated with 60-80 petroleum ether (500 ml).The solid precipitated title compound (10.50 g) was collected byfiltration and dried in vacuao.

¹H NMR δ: 7.79 (1H, dt, J 2.9+9.2 Hz), 8.04 (1H, d, J 4.4 Hz), 8.21 (1H,dd, J 5.7+9.3 Hz), 8.52 (1H, dd, J 2.9+11.2 Hz), 9.05 (1H, d, J 4.4 Hz).

m/z (API⁺): 192 (MH⁺).

EXAMPLES 1. 1-(1-Methyl-1H-indol-5-yl)-3-quinolin-4-ylurea and1-(1-methyl-1H-indol-5-yl)-3-quinolin4-yl)urea hydrochloride

Method 1

D3 (1.00 g) in dry toluene (20 ml) was heated slowly to reflux and thistemperature maintained for 1 h. The reaction mixture was cooled toambient temperature, 5-amino-1-methylindole (WO93/18028) (0.73 g) indichloromethane (30 ml) added and the mixture stirred under argon atambient temperature for 16 h. The resulting precipitate was collected byfiltration and washed with diethyl ether. Chromatography on silica geleluting with 50-100% ethyl acetate in hexane gave the title compound asa pale pink solid (0.50 g).

¹H NMR δ: 3.78 (3H, s), 6.39 (1H, d, J 2 Hz), 7.21 (1H, dd, J 2 Hz),7.31 (1H, d, J 2 Hz), 7.40 (1H, d, J 9 Hz), 7.67 (1H, m), 7.78 (2H, m),7.98 (1H, d, J 9 Hz), 8.26 (2H, m), 8.72 (1H, d, J2 Hz), 9.15 (1H, s),9.18 (1H, s).

m/z (API⁺): 317 (MH⁺).

The hydrochloride salt of the title compound was prepared as a yellowsolid.

m/z (API⁺): 317 (MH⁺).

Method 2

D4 (0.211 g) and carbonyldiimidazole (0.260 g) were stirred indichloromethane (4 ml) under argon at ambient temperature for 0.5 h. Thesolvent was removed at reduced pressure and 5-amino-1-methylindole(0.214 g) and dimethylformamide (10 ml) added. The mixture was heated at90° C. for 0.5 h under argon with stirring. The cooled mixture wastreated dropwise with water and the precipitated solid collected byfiltration. Chromatography on silica gel eluting with dichloromethanefollowed by recrystallisation from ethanol gave the title compound(0.065 g).

Method 3

A mixture of 4-quinolinecarboxylic acid (0.168 g), triethylamine (0.13ml) and diphenylphosphoryl azide (0.21 ml) in dimethylformamide (5 ml)was heated under argon at 63° C. for 0.5 h. The reaction was cooled toambient temperature and 1-methyl-5-aminoindole (0.130 g) added. Themixture was heated for a further 16 h then allowed to cool. Theresulting solution was partitioned between dichloromethane and water,the organic phase was dried (Na₂SO₄) and the solvent removed at reducedpressure. The residue was chromatographed on silica gel eluting with 20%ethyl acetate in hexane-acetone to give the title compound as a palepink solid (0.015 g).

2. 1-(1-Ethyl-1H-indol-5-yl)-3-quinolin-4-ylurea

From D3 (0.22 g) and 5-amino-1-ethyl-(1H)-indole D6(A) (0.18 g) thetitle compound (0.03 g), after recrystallisation from ethanol, wasprepared according to Example 1, Method 1.

¹H NMR δ: 1.36 (3H, t, J 7 Hz), 4.20 (2H, q, J 7 Hz), 6.41 (1H, d, J 3Hz), 7.25 (1H, dd), 7.39 (1H, d, J 3 Hz), 7.46 (1H, d, J 9 Hz), 7.83(2H, m), 7.98 (1H, t, J 8 Hz), 8.07 (1H, d, J 8 Hz), 8.57 (1H, d, J 6Hz), 8.76 (1H, d, J 8 Hz), 8.87 (1H, d, J 6 Hz), 10.13 (1H, s), 10.24(1H, bs).

m/z (API⁺): 331 (MH⁺).

3. 1-[1-(3-Phenylpropyl)-1H-indol-5-yl]-3-quinolin-4-ylurea

From D3 (0.22 g) and 5-amino-1-(3-phenylpropyl)-(1H)-indole D6(B) (0.28g) the title compound (0.14 g), after trituration with diethyl ether,was prepared according to Example 1, Method 1.

¹H NMR δ: 2.08 (2H, m), 2.57 (2H, t), 4.19 (2H, t), 6.41 (1H, d),7.18-7.32 (6H), 7.38-7.42 (2H, m), 7.64-7.80 (3H, m) 7.97 (1H, d),8.23-8.28 (2H, m), 8.71 (1H, d), 9.21 (2H, bs).

m/z (API⁺): 421 (MH⁺).

4. 1-(1-Benzyl-1H-indol-5-yl)-3quinolin-4-ylurea

From D4 (0.245 g) and 5-amino-1-benzyl-(1H)-indole D6(C) (0.37 g) thetitle compound (0.25 g), after column chromatography (silica gel,hexane→ethyl acetate) and trituration with diethyl ether, was preparedaccording to Example 1, Method 2.

¹H NMR δ: 5.41 (2H, s), 7.11-7.42 (8H, m), 7.51 (1H, d), 7.64-7.82 (3H,m), 7.98 (1H, d), 8.21 -8.27 (2H, m), 8.71 (1H, d), 9.14 (1H, bs), 9.23(1H, bs).

m/z (API⁺): 393 (MH⁺).

5. 1-[1-(3-Carboethoxypropyl)-1H-indol-5-yl]-3-quinolin-4-ylurea

From D3 (0.22 g) and 4-(5-aminoindol-1-yl)butyric acid ethyl esterD6(D), (0.27 g) the title compound (0.29 g) was prepared according toExample 1, Method 1.

¹H NMR δ: 1.34 (3H, t), 2.12-2.24 (2H, m), 2.44 (2H, t), 4.21 (2H, q),4.37 (2H, t), 6.59 (1H, d), 7.38 (1H, dd), 7.52 (1H, d), 7.63 (1H, d),7.82-7.98 (3H, m), 8.15 (1H, d), 8.42-8.46 (2H, m), 8.89 (1H, d), 9.40(2H, bs).

m/z (API⁺): 417 (MH⁺).

6. 1-[1-(3-Cyanopropyl)-1H-indol-5-yl]-3-quinolin-4-ylurea hydrochloride

From D3 (0.22 g) and 4-(5-aminoindol-1-yl)butyronitrile D6(E), (0.27 g)the title compound (0.29 g) was prepared according to Example 1, Method1.

¹H NMR δ: 2.09 (2H, t), 2.47 (2H, t), 4.25 (2H, t), 6.46 (1H, d, J 3Hz), 7.29 (1H, dd, J9+2 Hz), 7.40 (1H, d), 7.50 (1H, d), 7.86-7.94 (2H,m), 8.07-8.18 (2H, m), 8.77 (1H, d), 8.97 (1H, d), 9.16 (1H, d), 10.89(1H, s), 11.12 (1H, s).

m/z (API⁺): 370 (MH⁺).

7. 1-(1H-Indol-5-yl)-3quinolin-4-ylurea

From D3 (2.64 g) and 5-amino-(1H)-indole (1.77 g) the title compound(2.96 g) was prepared according to Example 1, Method 1.

¹H NMR δ: 6.30 (1H, d), 7.05 (1H, dd), 7.23-7.29 (2H, m), 7.55-7.69 (3H,7.88 (1H, d), 8.13-8.18 (2H, m), 8.61 (1H, d), 9.06 (2H, bs), 10.93 (1H,bs).

m/z (API⁺): 303 (MH⁺).

8. 1-(1-Methyl-1H-indolin-5-yl)-3-quinolin-4-ylurea and1-(1-methyl-1H-indolin-5-yl)-3-quinolin-4-ylurea dihydrochloride

From D3 (0.203 g) and 5-amino-1-methyl-(1H)-indoline D8(A) (0.150 g) thetitle free base was prepared according to Example 1, Method 1 (0.290 g).Free base ¹H NMR δ: 2.67 (3H, s), 2.87 (2H, t, J 8 Hz), 3.21 (2H, t, J 8Hz), 6.49 (1H, d, J 8 Hz), 7.11 (1H, dd, J2+8 Hz), 7.27 (1H, s), 7.65(1H, t), 7.76 (1H, t), 7.97 (1H, d), 8.22 (2H, m), 8.69 (1H, d), 9.11(2H, bs).

m/z (API⁺): 319 (MH⁺).

9. 1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-3-quinolin-4-ylureahydrochloride

From D3 (0.085 g) and 6-amino-1,4-benzodioxan (0.076 g) the titlecompound (0.08 g) was prepared according to Example 1, Method 1.

¹H NMR δ: 4.22-4.25 (4H, m), 6.85 (1H, d, J 9 Hz), 6.93 (1H, dd, J 2+9Hz), 7.20 (1H, d, J 2 Hz), 7.91 (1H, t), 8.07-8.17 (2H, m), 8.71 (1H, d,J 7 Hz), 8.98 (1H, d, J 7 Hz), 9.07 (1H, d, J 9 Hz), 10.84(1H, s), 11.01(1H, s).

m/z (API⁺): 322 (MH⁺).

10. 1-Benzo[1,3]dioxol-5-yl-3-quinolin-4-ylurea hydrochloride

From D3 (0.085 g) and benzo[1,3]dioxol-5-yl-ylamine (0.071 g) the titlecompound (0.12 g), was prepared according to Example 1, Method 1.

¹H NMR δ: 6.02 (2H, s), 6.91 (2H, s), 7.29 (1H, s), 7.88-7.94 (1H, m),8.07-8.18 (2H, m), 8.70 (1H, d, J 7 Hz), 8.98 (1H, d, J 7 Hz), 9.09 (1H,d, J 9 Hz), 10.96 (1H, s), 11.04 (1H, s).

m/z (API⁺): 308 (MH⁺).

11. 1-(4-Methoxyphenyl)-3-quinolin-4-ylurea

A solution of D4 (0.083 g) in dimethylformamide (0.5 ml) was treatedwith 4-methoxyphenyl isocyanate (0.085 g). The reaction mixture wasstirred for 16 h at ambient temperature, the solvent removed at reducedpressure and the residue was chromatographed on silica gel eluting with50-100% ethyl acetate in hexane to give the title compound (0.023 g).

¹H NMR δ: 3.73 (3H, s), 6.93 (2H, d, J 9 Hz), 7.45 (2H, d, J 9 Hz), 7.68(1H, m), 7.78 (1H, m), 7.99 (1H, d, J 8 Hz), 8.20 (2H, m), 8.7 (1H, d, J5 Hz), 9.15 (1H, s), 9.20 (1H, s).

m/z (API⁺): 294 (MH⁺).

12. 1-(3-Methylthiophenyl)-3-quinolin-4-ylurea Hydrochloride

A solution of 3-methylthiophenyl isocyanate (0.165 g) in toluene (4 ml)was added to a stirred suspension of D4 (0.144 g) in dichloromethane (8ml). The mixture was stirred for 48 h, diethyl ether (5 ml) added andthe precipitated solid collected by filtration. The solid was washedwith diethyl ether and hexane, suspended in methanol then treated withethereal HCl (1M) to give the title compound (0.22 g) as a yellow solid.

¹H NMR δ: 2.49 (3H, s), 6.98-7.01 (1H, m), 7.27-7.36 (2H, m), 7.57 (1H,s), 7.92 (1H, t), 8.80-8.18 (2H, m), 8.71 (1H, d), 8.99 (1H, d), 9.06(1H, d), 11.01 (2H, bs).

m/z (API⁺): 310 (MH⁺).

13. 1-(3,4-Dimethoxyphenyl)-3-quinolin-4-ylurea

D4 (0.124 g) and 3,4-dimethoxyphenyl isocyanate (Rasmussen et al, J.Med. Chem., 1972, 21, 1044) (0.157 g) in dichloromethane (6 ml) wastreated with 4-dimethylaminopyridine (0.005 g) in toluene (10 ml). Themixture was stirred for 16 h, solvent removed at reduced pressure andthe residue triturated with dichloromethane/diethyl ether (1:1) Theresulting yellow solid was collected by filtration to give the titlecompound (0.094 g).

¹H NMR δ: 3.73 (3H, s), 3.78 (3H, s), 6.90-6.99 (2H, m), 7.24 (1H, d, J1.67 Hz), 7.67 (1H, t), 7.77 (1H, t), 7.97 (1H, d), 8.19-8.24 (2H, m),8.71 (1H, d, J 5.1 Hz), 9.20 (2H, s).

m/z (API⁺): 324 (MH⁺).

14. 1-(4-Methylthiophenyl)-3-quinolin-4-ylurea hydrochloride

D4 (0.20 g) and 4-methylthiophenyl isocyanate (0.23 g) intoluene/dichloromethane (18 ml, 10:8) containing 4-dimethylaminopyridine(0.002 g) was stirred at room temperature for 16 h. The precipitatedsolid was separated by filtration, suspended in methanol and excessethereal HCl (1M) added. The title compound (0.313 g) isolated as ayellow solid was separated by filtration.

¹H NMR δ: 2.47 (3H, s), 7.30 (2H, d), 7.54 (2H, d), 7.91 (1H, dt),8.08-8.18 (2H, m), 8.72 (1H, d), 9.01 (1H, d), 9.06 (1H, d), 10.95 (1H,s), 11.04 (1H, s).

m/z (API⁺): 310 (MH⁺).

15. 1-(3-Ethylphenyl)-3-quinolin-4-ylurea

A mixture of D4 (0.072 g) and 3-ethylphenyl isocyanate (0.088 g) intoluene/dichloromethane (7 ml, 4:3) containing 4-dimethylaminopyridine(0.002 g) was stirred at room temperature for 16 h. The precipitatedsolid was separated by filtration, washed with diethyl ether and driedto give the title compound (0.032 g).

¹H NMR δ: 1.28 (3H, t), 2.70 (2H, q), 6.98 (1H, d), 7.33 (1H, t), 7.41(1H, m), 7.48 (1H, m), 7.76 (1H, t), 7.86 (1H, t), 8.07 (1H, d),8.28-8.33 (2H, m), 8.81 (1H, d), 9.34 (2H, bd).

m/z (API⁺): 292 (MH⁺).

16. 1-(4-Ethoxyphenyl)-3-quinolin-4-ylurea

From 4ethoxyphenyl isocyanate (0.098 g) and D4 (0.072 g) the titlecompound (0.099 g) was prepared according to the method of Example 15.

¹H NMR δ: 1.22 (3H, t), 3.90 (2H, q), 6.82 (2H, d), 7.32 (2H, d), 7.57(1H, t), 7.68 (1H, t), 7.88 (1H, d), 8.10-8.14 (2H, m), 8.62 (1H, d),9.04 (1H, s), 9.09 (1H, s).

m/z (API⁺): 308 (MH⁺).

17. 1-(4-N,N-Dimethylaminophenyl)-3-quinolin-4-ylunea and1-(4-N,N-Dimethylaminophenyl)-3-quinolin-4-ylurea dihydrochloride

From 4-dimethylaminophenyl isocyanate (0.097 g) and D4 (0.072 g) thetitle compound (0.097 g) was prepared according to the method of Example15.

¹H NMR δ: 2.78 (6H, s), 6.66 (2H, d), 7.26 (2H, d), 7.61 (1H, t), 7.68(1H, t), 7.90 (1H, d), 8.11-8.16 (2H, m) 8.62 (1H, d), 8.92 (1H, bs),9.06 (1H, bs).

m/z (API⁺): 307 (MH⁺).

The dihydrochloride was prepared.

¹H NMR δ: 3.06 (6H, s), 7.42 (2H, bs), 7.61 (2H, d), 7.93 (1H, t),8.09-8.20 (2H, m), 8.74 (1H, d), 9.00 (1H, d), 9.15 (1H, d), 11.18 (2H,bs).

18. 1-(4-Carboethoxyphenyl)-3-quinolin-4-ylurea

From 4-carboethoxyphenyl isocyanate (0.096 g) and D4 (0.072 g) the titlecompound (0.095 g) was prepared according to the method of Example 15.

¹H NMR δ: 1.33 (3H, t), 4.30 (2H, q), 7.68 (2H, d), 7.71-7.84 (2H, m),7.95-8.02 (3H, m), 8.19-8.29 (2H, m), 8.75 (1H, d), 9.35 (1H, s), 9.76(1H, s).

m/z (API⁺): 336 (MH⁺).

19. 1-(4-n-Butylphenyl)-3-quinolin-4ylurea

From 4-n-butylphenyl isocyanate (0.088 g) and D4 (0.072 g) the titlecompound (0.020 g) was prepared according to the method of Example 15.

¹H NMR δ: 0.90 (3H, t), 1.31 (2H, m), 1.55 (2H, m), 2.50 (2H, m), 7.16(2H, d), 7.42 (2H, d), 7.64-7.80 (2H, m), 7.99 (1H, d), 8.20-8.27 (2H,m), 8.72 (1H, d), 9.25 (2H, s).

m/z (API⁺): 320 (MH⁺).

20. 1-(4-Ethylphenyl)-3-quinolin-4-ylurea

From 4-ethylphenyl isocyanate (0.062 g) and D4 (0.072 g) the titlecompound (0.014 g) was prepared according to the method of Example 15.

¹H NMR δ: 1.06 (3H, t), 2.45 (2H, q), 7.07 (2H, d), 7.31 (2H, d), 7.56(1H, t), 7.66 (1H, t), 7.87 (1H, d), 8.08-8.13 (2H, m), 8.60 (1H, d),9.11 (2H, bd).

m/z (API⁺): 292 (MH⁺).

21. 1-(4-Trifluoromethoxyphenyl)-3-quinolin-4-ylurea

From 4-trifluoromethylphenyl isocyanate (0.122 g) and D4 (0.072 g) thetitle compound (0.025 g) was prepared according to the method of Example15.

¹H NMR δ: 7.42 (2H, d), 7.71 (2H, d), 7.73 (1H, t), 7.85 (1H, t), 8.06(1H, d), 8.26-8.29 (2H, m), 8.81 (1H, d), 9.48 (2H, bd).

m/z (API⁺): 348 (MH⁺).

22. 1-(4-Chlorophenyl)-3-quinolin-4-ylurea

From 4-chlorophenyl isocyanate (0.092 g) and D4 (0.072 g) the titlecompound (0.10 g) was prepared according to the method of Example 15.

¹H NMR δ: 7.47 (2H, d), 7.64 (2H, d), 7.76 (1H, t), 7.86 (1H, t), 8.07(1H, d), 8.26-8.30 (2H, m), 8.81 (1H, d), 9.32 (1H, s), 9.51 (1H, s).

m/z (API⁺): 298, 300 (MH⁺).

23. 1-(3-Chlorophenyl)-3-quinolin-4-ylurea

From 3-chlorophenyl isocyanate (0.092 g) and D4 (0.072 g) the titlecompound (0.093 g) was prepared according to the method of Example 15.

¹H NMR δ: 6.92 (1H, m), 7.12-7.24 (2H, m), 7.49-7.65 (3H, m), 7.83 (1H,d), 8.02-8.06 (2H, m), 8.58 (1H, d), 9.15 (1H, bs), 9.33 (1H, bs).

m/z (API⁺): 298, 300 (MH⁺).

24. 1-(3-Chloro-4-methylphenyl)-3-quinolin-4-ylurea

From 3-chloro-4-methylphenyl isocyanate (0.129 g) and D4 (0.072 g) thetitle compound (0.136 g) was prepared according to the method of Example15.

¹H NMR δ: 2.27 (3H, s), 7.14-7.31 (2H, m), 7.66 (1H, t), 7.72-7.78 (2H,m), 7.98 (1H, d), 8.16-8.20 (2H, m), 8.72 (1H, d), 8.23 (1H, s), 9.35(1H, s).

m/z (API⁺): 312, 314 (MH⁺).

25. 1-(3-Cyanophenyl)-3-quinolin-4-ylurea

From 3-cyanophenyl isocyanate (0.086 g) and D4 (0.072 g) the titlecompound (0.08 g) was prepared according to the method of Example 15.

¹H NMR δ: 7.46-7.62 (2H, m), 7.71-7.84 (3H, m), 8.01-8.09 (2H, m),8.22-8.24 (2H, d), 8.78 (1H, d), 9.40 (1H, s), 9.65 (1H, s).

m/z (API⁺): 289 (MH⁺).

26. 1-(3,4-Dichlorophenyl)-3-quinolin-4-ylurea

From 3,4-dichlorophenyl isocyanate (0.113 g) and D4 (0.072 g) the titlecompound (0.112 g) was prepared according to the method of Example 15.

¹H NMR δ: 7.40 (1H, dd), 7.61 (1H, d), 7.72 (1H, t), 7.81 (1H, t),7.99-8.05 (2H, m), 8.21 (2H, m), 8.77 (1H, d), 9.35 (1H, s), 9.60 (1H,s).

m/z (API⁺): 332, 334 (MH⁺).

27. 1-(3-Carboethoxyphenyl)-3-quinolin-4-ylurea Hydrochloride

From 3-carboethoxyphenyl isocyanate (0.096 g) and D4 (0.072 g) the titlecompound (0.027 g) was prepared according to the method of Example 15.

¹H NMR δ: 1.35 (3H, t), 4.35 (2H, q), 7.54 (1H, t), 7.69 (1H, d), 7.78(1H, d), 7.94 (1H, t), 8.09-8.18 (2H, m), 8.28 (1H, s), 8.73 (1H, d),9.01-9.05 (2H, m), 11.02 (1H, s), 11.13 (1H, s).

m/z (API⁺): 336 (MH⁺).

28. 1-(3-Bromo-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride

D3 (0.203 g) in toluene (10 ml) was warmed to 75° C. for 1 h and then to100° C. for 1 h. The reaction mixture was cooled to room temperature and3-bromo-4-methoxyaniline (H. Mitchell et al, J. Org. Chem., 1994, 59,682) (0.202 g) added in dichloromethane (5 ml). The mixture was stirredovernight and the solvent decanted. The solid was suspended in methanol(10 ml) and excess ethereal HCl (1M) added. The solid was collected byfiltration and the residue washed with methanol and diethyl ether togive the title compound (0.20 g).

¹H NMR δ: 3.65 (3H, s), 6.93 (1H, d, J 9 Hz), 7.20 (1H, dd, J 3+9 Hz),7.54 (1H, t, J 7 Hz), 7.66 (1H, 8 Hz), 7.72 (1H, d, J 3 Hz), 8.82 (1H,d, J 8 Hz), 8.12 (1H, d, J 5.6 Hz), 8.21 (1H, d, J 8 Hz), 8.59 (1H, d, J5.5 Hz), 9.54 (2H, s).

m/z (API⁺): 372, 374 (MH⁺).

29. 1-(4-Trifluoromethylthiophenyl)-3-quinolin-4-ylurea hydrochloride

From 4-trifluoromethylthioaniline (0.193 g) and D3 (0.198 g) the titlecompound (0.14 g) was prepared according to the method of Example 28.

¹H NMR δ: 7.74 (4H, s), 7.93 (1H, t), 8.08-8.19 (2H, m), 8.71 (1H, d),9.02 (1H, d), 9.07 (1H, d), 11.11 (1H, bs), 11.39 (1H, s).

m/z (API⁺): 364 (MH⁺).

30. 1-(8-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3-quinolin-4-ylureahydrochloride

From 7-amino-3,4-dihydro-2H-naphthalen-1-one (0.161 g) and D3 (0.198 g)the title compound (0.14 g) was prepared according to the method ofExample 28.

¹H NMR δ: 2.03-2.09 (2H, m), 2.62 (2H, t), 2.92 (2H, t), 7.38 (1H, d),7.69 (1H, dd), 7.92 (1H, t), 8.08-8.17 (3H, 8.73 (1H, d), 9.01 (1H, d),9.08 (1H, d), 11.08 (1H, s), 11.12 (1H, s).

m/z (API⁺): 332 (MH⁺).

31. 1-(3-Chloro-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride

From 3-chloro-4-methoxyaniline (0.082 g) and D3 (0.095 g) the titlecompound (0.12 g), after trituration with methanol, was preparedaccording to the method of Example 28.

¹H NMR (CD₃OD) δ: 3.98 (3H, s), 7.17 (1H, d), 7.49 (1H, dd), 7.82 (1H,d), 8.03 (1H, m), 8.19 (2H, m), 8.61(1H, d), 8.93 (2H, s).

32. 1-(4-N-Morpholin-4-ylphenyl)-1-quinolin-4-ylurea dihydrochloride

D4 (0.231 g) was added in portions to carbonyl diimidazole (0.259 g) indichloromethane (20 ml) and the mixture stirred at room temperature for2 h. Solvent was removed at reduced pressure and dimethylformamide (8ml) and 4-morpholinoaniline (0.285 g) added. The mixture was heated at100° C. for 1 h, cooled to room temperature and poured into water. Theprecipitated solid was collected by filtration and washed with water,diethyl ether and hexane. The solid was suspended in methanol andtreated with excess ethereal HCl (1M). The mixture was stirred for 15min, filtered, the residue washed with methanol, dissolved in hotethanol (150 ml), filtered and solvent volume reduced to (75 ml). Thecrystallised solid was collected by filtration and washed with methanolto give the title compound (0.185 g).

¹H NMR (d₆-DMSO and D₂O) δ: 3.39 (4H, bs), 3.93 (4H, bs), 7.44 (2H, d),7.60 (2H, d), 7.92 (1H, t), 8.07-8.19 (2H, m), 8.73 (1H, d), 8.97 (1H,d), 9.06 (1H, d).

m/z (API⁺): 349 (MH⁺).

33. 1-(3-Acetylphenyl)-3-quinolin-4-ylurea hydrochloride

A mixture of D4 (0.100 g) and 3-acetylphenyl isocyanate (0.112 g) intoluene/dichloromethane (12 ml, 1:2) containing 4-dimethylaminopyridine(0.002 g) was stirred at room temperature for 16 h. The precipitatedsolid was separated by filtration, suspended in ethyl acetate and excessethereal HCl (1M) added. The precipitated pale yellow title compound(0.027 g) was separated by filtration.

¹H NMR δ: 2.60 (3H, s), 7.55 (1H, t), 7.72-7.81 (2H, m), 7.93 (1H, t),8.08-8.20 (3H, m), 8.73 (1H, d), 9.01 (1H, d), 9.06 (1H, d), 11.06 (1H,d), 11.17 (1H, s).

m/z (API⁺): 306 (MH⁺).

34. 1-(4-Phenylaminophenyl)-3-quinolin-4-ylurea dihydrochloride

D4 (0.192 g) in dichloromethane (5 ml) was added dropwise to a stirredsuspension of carbonyl diimidazole (0.169 g) in dichloromethane (5 ml).After 30 min solvent was removed at reduced pressure anddimethylformamide (8 ml) and 4-aminodiphenylamine (0.192 g) added. Themixture was heated for 30 min at 95° C. cooled to room temperature andpoured into water (150 ml). The black oil obtained was triturated withmethanol to give a grey solid which was suspended in methanol and excessethereal HCl (1M) added to give the title compound (0.212 g).

¹H NMR δ: 6.79 (1H, t), 7.02-7.25 (6H, m), 7.46 (2H, d), 7.91 (1H, t),8.08-8.20 (2H, m), 8.75 (1H, d), 8.97 (1H, d), 9.17 (1H, d), 10.96 (1H,d), 11.17 (1H, s).

m/z (API⁺): 355 (MH⁺).

35. 1-[3-Oxazo-5-yl)phenyl]-3-quinolin-4-ylurea

From D4 (0.20 g) and 3-(1,3-oxazol-5-yl)aniline (0.222 g), the titlecompound (0.135 g), following recrystallisation from methanol, wasprepared according to the method of Example 34.

¹H NMR δ: 7.39-7.46 (3H, m), 7.67-7.72 (2H, m), 7.79 (1H, t), 7.96-8.02(2H, m), 8.25 (2H, m), 8.49 (1H, s), 8.48 (1H, d), 9.31 (1H, bs), 9.49(1H, bs).

m/z (API⁺): 331 (MH⁺).

36.1-[4-((4,6-Dimethylpyrimidin-2-yl)methylamino)phenyl]-3-quinolin-4-ylureadihydrochloride

From D4 (0.10 g) andN-methyl-N-(4,6-dimethylpyrimidin-2-yl)-1,4-phenylenediamine (0.158 g),followed by column chromatography (silica gel, 1:1 ethylacetate/hexane→ethyl acetate), combining the appropriate fractions andremoving the solvent under reduced pressure, the title compound (0.057g) was prepared according to the method of Example 34.

¹H NMR δ: 2.34 (6H, s), 2.51 (3H, s), 6.73 (1H, s), 7.40 (2H, d), 7.65(2H, d), 7.92 (1H, t), 8.13 (1H, t), 8.24 (1H, d), 8.77 (1H, d), 9.01(1H, d), 9.28 (1H, d), 11.36 (1H, s), 11.52 (1H, s).

m/z (API⁺): 399 (MH⁺).

37. 1-(4-Pyrrolidinylphenyl-3-quinolin-4-ylurea dihydrochloride

From D4 (0.10 g) and 4-pyrrolidinylaniline (0.112 g) the title compound(0.078 g) was prepared according to the method of Example 34.

¹H NMR δ: 2.00 (4H, m), 3.34 (4H, m), 6.88 (2H, bs), 7.47 (2H, d), 7.90(1H, t), 8.08-8.20 (2H, m), 8.74 (1H, d), 8.96 (1H, d), 9.17 (1H, d),10.93 (1H, bs), 11.16 (1H, s).

m/z (API⁺): 333 (MH⁺).

38. 1-(3-Dimethylaminophenyl)-3-quinolin-4-ylurea dihydrochloride

From D4 (0.10 g) and N,N-dimethylbenzene-1,3-diamine (0.095 g), thetitle compound (0.014 g) after column chromatography (silica gel, 1:1ethyl acetate/hexane→ethyl acetate) was prepared according to the methodof Example 34.

¹H NMR δ: 2.93 (6H, s), 6.86 (1H, bd), 7.10 (1H, d), 7.26 (1H, t), 7.38(1H, bs), 7.82 (1H, t), 7.99-8.11 (2H, m), 8.65 (1H, d), 8.88 (1H, d),9.06 (1H, d), 11.11 (2H, bs).

m/z (API⁺): 307 (MH⁺).

39. 1-(4-Carboxamidophenyl)-3-quinolin-4-ylurea hydrochloride

From D4 (0.10 g) and 4-aminobenzamide (0.095 g), followed by columnchromatography (silica gel, 1:1 ethyl acetate/hexane ethyl acetate), thetitle compound (0.09 g) was prepared according to the method of Example34.

¹H NMR δ: 7.30 (1H, bs), 7.64 (2H, d), 7.91 (4H, d), 8.09-8.19 (2H, m),8.73 (1H, d), 9.03 (1H, d), 9.06 (1H, d), 11.08 (1H, bs), 11.20 (1H, s).

m/z (API⁺): 307 (MH⁺).

40. 1-(4-N,N-Diethylaminophenyl)-3-quinolin-4-ylurea dihydrochloride

From D4 (0.085 g) and N,N-diethylbenzene-1,4-diamine (0.097 g), thetitle compound (0.04 g) was prepared according to the method of Example34.

¹H NMR δ: 1.05 (6H, t), 3.52 (4H, obscured by HOD resonance), 7.76 (4H,bs), 7.93 (1H, t), 8.12 (1H, t), 8.20 (1H, d), 8.74 (1H, d), 9.02 (1H,d), 9.19 (1H, d), 11.29 (1H, bs), 11.59 (1H, bs), 12.36 (1H, bs).

m/z (API⁺): 335 (MH⁺).

41. 1-(4-Dimethylaminophenyl)-3-(5-methoxyquinolin-4-yl)ureadihydrochloride

A solution of D15 (0.143 g) in dichloromethane (4 ml) was treated with4-dimethylaminophenyl isocyanate (0.133 g, 0.58 mmol) in toluene (4 ml).The reaction was stood at room temperature for 16 h, solvent removed atreduced pressure and the residue precipitated from dichloromethanesolution (5 ml) with diethyl ether (20 ml). The precipitated compound(free base) was separated by filtration and suspended in methanol. TheHCl salt was prepared to give the title compound (0.150 g).

¹H NMR δ: (free base) 2.87 (6H, s), 3.97 (3H, bs), 6.75 (2H, d), 7.04(1H, d), 7.30 (2H, d), 7.50-7.63 (2H, m), 8.32 (1H, d), 8.59 (1H, d),9.47 (1H, bs), 10.01 (1H, s).

m/z (API⁺): 295 (MH⁺).

42. 1-(4-Dimethylaminophenyl)-3-(8-bromoquinolin-4-yl)ureadihydrochloride

D17 (0.25 g) in toluene (15 ml) was heated at 75° C. for 2 h. Themixture was cooled to room temperature andN,N-dimethylbenzene-1,4-diamine (0.122 g) in dichloromethane (5 ml)added. After stirring for 16 h, the precipitated solid was collected byfiltration to give the title compound (free base). The HCl salt wasprepared to give the title compound.

¹H NMR δ: 3.04 (6H, s), 7.59-7.71 (5H, m), 8.33 (1H, d), 8.67 (1H, d),8.85 (1H, d), 9.13 (1H, d) 11.17 (1H, s), 11.47 (1H, s).

m/z (API⁺): 385, 387 (MH⁺).

43. 1-(4-Dimethylaminophenyl)-3-(8-methoxyquinolin-4-yl)ureadihydrochloride

From D23 (0.087 g) and 4-dimethylaminophenyl isocyanate (0.089 g) thetitle compound (0.080 g) was prepared according to the method of Example41.

¹H NMR δ: 3.08 (6H, s), 4.15 (3H, s), 7.56-7.68 (5H, m), 7.84 (1H, t),8.73-8.84 (3H, m), 11.21 (1H, s), 11.52 (1H, bs).

m/z (API⁺): 337 (MH⁺).

44. 1-(2-Chlorophenyl)-3-quinolin-4-ylurea

From 2-chlorophenyl isocyanate (0.077 g) and D4 (0.072 g) the titlecompound (0.065 g) was prepared according to the method of Example 15.

¹H NMR δ: 7.09 (1H, t), 7.34 (1H, t), 7.50 (1H, d), 7.66 (1H, t), 7.77(1H, t), 7.98 (1H, d), 8.16 (1H, d), 8.20 (1H, d), 8.29 (1H, d), 8.72(1H, d), 9.10 (1H, s), 9.81 (1H, s).

m/z (API⁺): 298, 300 (MH⁺).

45. 1-(2-Methylphenyl)-3-quinolin-4-ylurea

From 2-methylphenyl isocyanate (0.067 g) and D4 (0.072 g) the titlecompound (0.086 g) was prepared according to the method of Example 15.

1H NMR δ: 2.16 (3H, s), 6.92 (1H, t), 7.04-7.15 (2H, m), 7.58 (1H, t),7.68 (1H, t), 7.76 (1H, d), 7.90 (1H, d), 8.13 (1H, d), 8.18 (1H, d),8.54 (1H, s), 8.62 (1H, d), 9.93 (1H, s).

m/z (API⁺): 278 (MH⁺).

46. 1-(4-Methoxy-2-methylphenyl)-3-quinolin-4-ylurea hydrochloride

4-Methoxy-2-methyl aniline in tetrahydrofuran (10 ml) was added to astirred suspension of carbonyl diimidazole (0.26 g) in tetrahydrofuran(10 ml). After stirring for 1 h, solvent was removed at reducedpressure, the residue dissolved in dimethylformamide (8 ml) and4-aminoquinoline (0.23 g) added. The mixture was heated at 95° C. for 30min, cooled and poured into water and extracted with dichloromethane(2×20 ml). The combined organic phase was washed with water, dried(Na₂SO₄) and solvent removed at reduced pressure. The residue was columnchromatographed (silica gel ethyl acetate/hexane mixture) to give, afterconversion to the hydrochloride salt the title compound (0.02 g).

¹H NMR δ: 2.33 (3H, s), 3.75 (3H, s), 6.80 (1H, dd, J 2.54+11 Hz), 6.85(1H, m), 7.50 (1H, d, J 8.7 Hz), 7.89-7.95 (1H, m), 8.08-8.18 (2H, m),8.71 (1H, d, J 6.8 Hz), 8.97 (1H, d, J 6.8 Hz), 9.13 (1H, d, J 8.7 Hz),9.92 (1H, bs), 11.23 (1H, bs).

m/z (API⁺): 308 (MH⁺).

47. 1-(1-Hydroxy-1-ethylphen-3-yl)-3-quinolin-4-ylurea hydrochloride

Example 33 (0.460 g) in ethanol/water 10%, 40 ml) was treated withsodium borohydride (0.126 g). The mixture was stirred at roomtemperature overnight, acidified cautiously with HCl (5M), neutralisedwith sodium carbonate and solvent removed at reduce pressure. Theresidue was triturated with water, filtered, dried and converted to thetitle compound HCl salt (0.27 g) according to the method of Example 46.

¹H NMR δ: 1.34 (3H, d), 4.72 (1H, q), 5.22 (1H, bs), 7.01 (1H, d), 7.31(1H, t), 7.42 (1H, d), 7.51 (1H, s), 7.68 (1H, t), 7.78 (1H, t), 7.99(1H, d), 8.23-8.26 (2H, m), 8.73 (1H, d), 9.35 (2H, bs).

m/z (API⁺): 308 (MH⁺).

48. 1-(3-Trifluoromethylthiophenyl)-3-quinolin-4-ylurea hydrochloride

From 3-trifluoromethylthiophenyl isocyanate (0.152 g) and D4 (0.100 g)the title compound was prepared according to the method of Example 15(0.105 g).

¹H NMR δ: 7.45 (1H, d), 7.56 (1H, t), 7.71 (1H, d), 7.93 (1H, t),8.06-8.19 (3H, m), 8.73 (1H, d), 9.025 (1H, d), 9.10 (1H, d), 11.13 (1H,bs), 11.39 (1H, bs).

m/z (API⁺): 364 (MH⁺).

49. 1-(3,5-Dichlorophenyl)-3-quinolin-4-ylurea hydrochloride

From 3,5-dichlorophenyl isocyanate (0.188 g) and D4 (0.144 g) the titlecompound (0.130 g) was prepared according to the method of Example 15.

¹H NMR δ: 7.31 (1H, m), 7.60 (2H, m), 7.93 (1H, t), 8.08-8.24 (2H, m),8.70 (1H, d), 9.03-9.12 (2H, m), 11.12 (1H, bs), 11.59 (1H, bs).

m/z (API⁺): 332, 334 (MH⁺).

50. 1-(1-Methylbenzimidazol-6-yl)-3-quinolin-4-ylurea dihydrochloride

A mixture of 1-methyl-6-benzimidazole carboxylic acid (0.230 g),triethylamine (0.17 ml) and diphenyl phosphoryl azide (0.33 g) werecombined in toluene (10 ml) and warmed to 65° C. for 30 min. D4 (0.17 g)was added and heating continued at 65° C. for 16 h. Solvent was removedat reduced press,re and the residue column chromatographed (silica gel(20%→100% ethyl acetate/pentane) to give after conversion to the HClsalt the title compound (0.050 g).

1H NMR δ: 4.05 (3H, s), 7.57 (1H, d, J 2+9 Hz), 7.90 (2H, m), 8.12 (1H,dd, J 7+7 Hz), 8.29 (2H, m), 8.79 (1H, d, J 7 Hz), 9.02 (1H, d, J 7 Hz),9.32 (1H, d, J 9 Hz), 9.44 (1H, s), 11.47 (1H, s), 11.93 (1H, s).

m/z (API⁺): 317 (MP^(+).)

51. 1-(4-Methoxy-3-trifluoromethylphenyl)-3-quinolin-4-ylureahydrochloride

From D3 (0.198 g) and 4-methoxy-3-trifluoromethylaniline (0.191 g) thetitle compound (0.218 g) was prepared according to the method of Example28.

1H NMR δ: 3.69 (3H, s), 7.12 (1H, d), 7.51 (1H, dd), 7.70-7.54 (2H, m),7.88-7.98 (2H, m), 8.52 (1H, d), 8.80 (1H, d), 8.89 (1H, d), 10.89 (1H,s), 10.99 (1H, d).

m/z (API⁺): 362 (MH⁺).

52. N-Methyl-3-(3-quinolin-4-ylureido)benzamide hydrochloride

From D3 (0.198 g) and 3-N-methylcarboxamidoaniline (0.191 g) the titlecompound salt (0.160 g) was prepared according to the method of Example28.

¹H NMR δ: 2.80 (3H, d), 7.45 (1H, t), 7.54 (1H, d), 7.71 (1H, d), 7.91(1H t), 8.05-8.24 (3H, m), 8.50 (1H, d), 8.76(1H, d), 9.01 (1H, d), 9.17(1H, d), 11.23 (1H, s), 11.26 (1H, s).

m/z (API⁺): 321 (MH⁺).

53. 1-(4-Dimethylaminomethylphenyl)-3-quinolin-4-ylurea dihydrochloride

From D3 (0.15 g) and N,N-dimethylbenzene-1,4-diamine (0.113 g) the titlecompound (0.125) was prepared according to the method of Example 28.

¹H NMR δ: 2.41 (6H, s), 3.88 (2H, s), 7.46 (2H, d), 7.60 (2H, d), 7.93(1H, t), 8.09-8.19 (2H, m), 8.74 (1H, d), 9.00 (1H, d), 9.10 (1H, d),11.11 (1H, s), 11.14 (1H, s).

m/z (API⁺): 321 (MH⁺).

54. 1-(4-Hydroxymethylphenyl)-3-quinolin-4-ylurea hydrochloride

From D3 (0.198 g) and 4-aminobenzyl alcohol (0.124 g) the title compound(0.096 g) was prepared according to the method of Example 28.

¹H NMR δ: 4.47 (2H, s), 7.32 (2H, d), 7.54 (2H, d), 7.92 (1H, t),8.08-8.21 (2H, m), 8.73 (1H, d), 8.99 (1H, d), 9.09 (1H, d), 10.96 (1H,s), 11.08 (1H, s).

m/z (API⁺): 294 (MH⁺).

55. 1-(4-N,N-Dimethylaminophenyl)-3-(7-methoxy)quinolin-4-ylureahydrochloride

From 4-N,N-dimethylaminophenyl isocyanate (0.089 g) and4-amino-7-methoxyquinoline (Spaeth et al, Chem. Ber., 1924, 57, 1250)(0.087 g) the title compound (0.044 g), after column chromatography(silica gel, 20→100% ethyl acetate/hexane eluant) and conversion to theHCl salt, was prepared according to the method of Example 15.

¹H NMR δ: 3.08 (6H, s), 4.00 (3H, s), 7.51-7.66 (6H, m), 8.59 (1H, d, J6.9 Hz), 8.87 (1H, d, J 6.9 Hz), 9.10 (1H, d, J 9.3 Hz), 11.18 (1H, bs),11.30 (1H, bs).

m/z (API⁺): 337 (MH⁺).

56. 1-(3-Fluoro-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride

From D3 (0.100 g) and 3-fluoro-4-methoxyaniline (0.073 g) the titlecompound (0.056 g) was prepared according to the method of Example 28.

¹H NMR δ: 3.83 (3H, s), 7.15-7.22 (2H, m), 7.57 (1H, d), 7.90-7.96 (1H,m), 8.08-8.17 (2H, m), 8.69 (1H, d), 8.99 (2H, d), 10.86 (1H, s), 10.93(1H, s)

m/z (API⁺): 312 (MH⁺).

57. 1-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-quinolin-4-ylureahydrochloride

From D3 (0.100 g) and 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylamine(0.094 g) the title compound (0.087 g) was prepared according to themethod of Example 28.

¹H NMR δ: 2.10 (2H, m), 4.07-4.16 (4H, m), 6.97 (1H, d), 7.10 (1H, dd),7.27 (1H, d), 7.88-7.94 (1H, m), 8.08-8.18 (2H, m), 8.71 (1H, d), 8.98(1H, d), (1H, d), 10.99 (1H, s), 11.06 (1H, s).

m/z (API⁺): 336 (MH⁺).

58. 1-(3-Chloro-4-dimethylaminophenyl)-3-quinolin-4-ylureadihydrochloride

From D3 (0.198 g) and 3-chloro-4-N,N-dimethylbenzene-1,4-diamine (0.170g) the title compound (0.190 g) was prepared according to the method ofExample 28.

¹H NMR δ: 2.86 (6H, s), 7.41-7.50 (2H, m), 7.77 (1H, d), 7.91 (1H, t),8.12 (1H, t), 8.21 (1H, d), 8.74 (1H, d), 9.00 (1H, d), 9.22 (1H, d),11.29 (1H, bs), 11.55 (1H, bs).

m/z (API⁺): 341, 343 (MH⁺).

59. 1-Quinolin-4-yl-3-(4-[1,2,4]triazol-1-ylphenyl)urea hydrochloride

From D3 (0.099 g) and 4-[1,2,4-triazol-1-yl]aniline (0.080 g) the titlecompound (0.108 g) was prepared according to the method of Example 28.

¹H NMR δ: 7.76 (2H, d, J 9 Hz), 7.87-7.96 (3H, m), 8.09-8.25 (3H, m),8.77 (1H, d, J 7 Hz), 9.03 (1H, d, J 7 Hz), 9.24 (1H, d, J 9 Hz), 9.29(1H, s), 11.32 (1H, s), 11.55 (1H, s).

m/z (API⁺): 331 (MH⁺).

60. 1-(Benzothiazol-6-yl)-3-quinolin-4-ylurea hydrochloride

From D3 (0.099 g) and 6-aminobenzothiazole (0.78 g) the title compound(0.10 g) was prepared according to the method of Example 28.

¹H NMR δ: 7.60 (1H, dd), 7.78 (1H, t), 7.92 (1H, t), 8.04-8.09 (2H, m),8.40-8.48 (2H, m), 8.58 (1H, d), 8.86 (1H, d), 9.28 (1H, s), 10.07 (1H,bs), 10.32 (1H, s).

m/z (API⁺): 321 (MH⁺).

61. 1-Benzo[b]thiophen-5-yl-3-quinolin-4-ylurea hydrochloride

From D3 (0.198 g) and 5-aminobenzthiophene sulphate salt (0.149 g) thetitle compound (0.100 g) was prepared according to the method of Example28 except that triethylamine (0.165 ml) was added to the reactionmixture with the 5-aminobenzthiophene sulphate.

¹H NMR δ: 7.42-7.48 (2H, m), 7.75-7.80 (2H, m), 7.89 (1H, t), 7.97 (1H,d), 8.03 (1H, d), 8.20 (1H, d), 8.30-8.39 (2H, m), 8.82 (1H, d), 9.56(2H, bs).

m/z (API⁺): 320 (MH⁺).

62. 1-(1-Methyl-1,2,3,4-tetrahydroquinolin-6-yl-3-quinolin-4-ylureadihydrochloride

From D3 (0.089 g) and 1-methyl-6-amino-1,2,3,4-tetrahydroquinolinedihydrochloride (0.089 g) the title compound (0.090 g) was preparedaccording to the method of Example 28 except that triethylamine (0.09 g)was added to the reaction mixture with the1-methyl-6-amino-1,2,3,4-tetrahydroquinoline dihydrochloride.

¹H NMR δ: 2.04 (2H, m), 2.83 (2H, m), 3.03 (3H, s), 3.37 (2H, m), 7.20(1H, bs), 7.35 (1H, s), 7.43 (1H, d), 7.90 (1H, s), 8.11 (1H, t), 8.20(1H, d), 8.74 (1H, d), 8.98 (1H, d), 9.23 (1H, d), 11.29 (2H, s).

m/z (API⁺): 333 (MH⁺).

63. 1-(4-N-Ethyl-N-isopropylaminophenyl)-3-quinolin-4-ylureadihydrochloride

From D3 (0.198 g) and N-ethyl-N-isopropylbenzene-1,4-diaminehydrochloride (0.215 g) the title compound (0.290 g) was preparedaccording to the method of Example 28 except that triethylamine (0.100g) was added to the reaction mixture with theN-ethyl-N-isopropylbenzene-1,4-diamine hydrochloride.

¹H NMR δ: (free base) 1.03 (3H, t), 1.07 (6H, d), 3.14 (2H, q), 3.93(1H, m), 6.69 (2H, d), 7.26 (2H, d), 7.62 (1H, t), 7.72 (1H, t), 7.92(1H, dd), 8.15-8.21 (2H, m), 8.65 (1H, d), 8.91 (1H, s), 9.09 (1H, s).

m/z (API⁺): 349 (MH⁺).

64.1-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-quinolin-4-ylureadihydrochloride

From D3 (0.150 g) and 4-methyl-7-amino-3,4-dihydro-(1,4)-benzoxazine(0.124 g) (D. R. Shridhar, M. Jogibhukta, V. S. Krishnan; Org. Prep.Proced. Int. 1982, 14, 195) the title compound (0.186 g) was preparedaccording to the method of Example 28.

¹H NMR δ: 2.85 (3H, s), 3.24 (2H, m), 4.28 (2H, m), 6.78 (1H, d), 6.95(1H, dd), 7.05 (1H, d), 7.90 (1H, t), 8.11 (1H, t), 8.18 (1H, d), 8.72(1H, d), 8.95 (1H, d), 9.17 (1H, d), 10.91 (1H, s), 11.14 (1H, s).

m/z (API⁺): 335 (MH⁺).

65. 1-(2-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-3-quinolin-4-ylurea hydrochloride

From D3 (0.10 g) and 2-methyl-7-amino-1,2,3,4-tetrahydroisoquinoline(0.081 g) the title compound (0.095 g) was prepared according to themethod of Example 28.

¹H NMR δ: 2.90 (3H, d), 3.03-3.39 (4H, m), 4.23-4.55 (2H, m), 7.26 (1H,d), 7.44-7.49 (2H, m), 7.91 (1H, t), 8.12 (1H, t), 8.22 (1H, d), 8.74(1H, d), 9.00 (1H, d), 9.27 (1H, d), 11.35 (1H, s), 11.45 (1H, s).

m/z (API⁺): 333 (MH⁺).

66. 1-(1,2-Dimethyl-1H-indol-5-yl)-3-quinolin-4-ylurea hydrochloride

From D3 (0.321 g) and 5-amino-1,2-dimethylindole (0.272 g) the titlecompound (0.262 g) was prepared according to the method of Example 28.

¹H NMR δ: 2.39 (3H, s), 3.65 (3H, s), 6.18 (1H, s), 7.11 (1H, dd), 7.33(1H, d), 7.64-7.70 (2H, m), 7.77 (1H, t), 7.97 (1H, d), 8.22-8.27 (2H,m), 8.71 (1H, d), 9.10 (1H, s), 9.18 (1H, s).

m/z (API⁺): 331 (MH⁺).

67. 1-(2,3-Dihydro-1H-indol-5-yl)-3-quinolin-4-yl urea dihydrochloride

a) From D3 (0.50 g) and 5-amino-1-tert-butoxycarbonylindoline (0.565 g)5-(3-quinolin-4-ylureido)-2,3-dihydroindole-1-carboxylic acid tert butylester (0.79 g) was prepared according to the method of Example 28.

m/z (API⁺): 405 (MH⁺).

b) 5-(3-Quinolin-4-ylureido)-2,3-dihydroindole-1-carboxylic acid tertbutyl ester (0.10 g) in methanol (4 ml) was treated with 1M HCl indiethyl ether (1 ml) and stirred for 1 hr. Additional HCl (2 ml, 1M indiethyl ether) was added followed by a further aliquot (2 ml) after 20h. The mixture was stiffed for a further 6 hr and solvent removed atreduced pressure. The product was triturated with methanol (50 ml) andthe solid collected by filtration to give the title compound (0.045 g).

¹H NMR δ: 3.23 (2H, t), 3.73 (2H, t), 7.40 (1H, d), 7.53 (1H, dd), 7.70(1H, s), 7.91 (1H, t), 8.12 (1H, t), 8.19 (1H, d), 8.73 (1H, d), 9.01(1H, d), 9.21 (1H, d) 11.27 (1H, s), 11.48 (1H, s).

m/z (API⁺): 305 (MH⁺).

68. 1-(4-Dimethylaminophenyl)-3-(7-bromoquinolin-4-yl)ureadihydrochloride

From D25 (0.217 g) and N,N-dimethylbenzene-1,4-diamine (0.106 g) thetitle compound (0.260 g) was prepared according to the method of Example28.

¹H NMR δ: 3.08 (6H, s), 7.52 (2H, bs), 7.62 (2H, d), 8.10 (1H, dd), 8.39(1H, d), 8.71 (1H, d), 9.00 (1H, d), 9.10 (1H, d), 11.24 (1H, bs), 11.30(1H, s).

m/z (API⁺): 385, 387 (MH⁺).

69. 1-(4-Dimethylaminophenyl)-3-(6-bromoquinolin-4-ylureadihydrochloride

From D27 (0.20 g) and N,N-dimethylamino-benzene-1,4-diamine (0.98 g) thetitle compound (0.170 g) was prepared according to the method of Example28.

¹H NMR δ: (2.86, 6H, s), 6.74 (2H, d), 7.34 (2H, d), 7.85-7.96 (2H, m),8.27 (1H, d), 8.47 (1H, d), 8.72(1H, d), 8.92 (1H, s), 9.17 (1H, s).

m/z (API⁺): 385, 387 (MH⁺).

70. 1-(3-Ethoxyphenyl)-3-quinolin-4-ylurea hydrochloride

From 3-ethoxybenzoic acid (0.115 g) and D4 (0.10 g) the title compound(0.040 g) was prepared according to the method of Example 50.

¹H NMR δ: 1.35 (3H, t, J 7 Hz), 4.03 (2H, q, J 7 Hz), 6.67 (1H, dd, J2+8 Hz), 7.08 (1H, d, J 8 Hz), 7.26 (2H, m), 7.92 (1H, m), 8.13 (2H, m),8.73 (1H, d, J 7 Hz), 9.00 (1H, d, J7 Hz), 9.12 (1H, d, J8 Hz), 11.05(1H, s), 11.09 (1H, s).

m/z (API⁺): 308 (MH⁺).

71. 1-(4-Ethylthiophenyl)-3-quinolin-4-yl urea hydrochloride

From 4-ethylthiobenzoic acid (0.186 g) and D4 (0.144 g) the titlecompound (0.130 g) was prepared to the method of Example 50.

¹H NMR δ: 1.22 (3H, t, J 7 Hz), 2.95 (2H, q, J 7 Hz), 7.37 (2H, d, J 8Hz), 7.56 (2H, d, J 8 Hz), 7.92 (1H, m), 8.13 (2H, m), 8.72 (1H, d, J 7Hz), 9.00 (1H, d, J 7 Hz), 9.06 (1H, d, J 9 Hz), 10.99 (1H, s), 11.03(1H, s).

m/z (API⁺): 324 (MH⁺).

72.1-(3-Bromo-4-dimethylaminophenyl)-3-quinolin-4-ylurea-dihydrochloride

From 3-bromo-4-dimethylaminobenzoic acid (0.200 g) and D4 (0.132 g) thetitle compound (0.145 g) was prepared according to the method of Example50.

¹NMR δ: 2.83 (6H, s), 7.42 (1H, d, J 9 Hz), 7.53 (1H, dd, J 2+9 Hz),7.91 (2H, m), 8.12 (1H, dd, J 7+7 Hz), 8.23 (1H, d, J 8 Hz), 8.74 (1H,d, J 7 Hz), 9.01 (1H, d, J 7 Hz), 9.24 (1H, d, J 8 Hz), 11.30 (1H, s),11.55 (1H, s).

m/z (API⁺): 385, 387 (MH⁺).

73. 1-(4-Methoxy-3-methylphenyl)-3-quinolin-4-ylurea hydrochloride

From 4-methoxy-3-methylbenzoic acid (0.200 g) and D4 (0.144 g) the titlecompound (0.130 g) was prepared according to the method of Example 50.

¹H NMR δ: 2.16 (3H, s), 3.78 (3H, s), 6.93 (1H, d, J 9 Hz), 7.32 (1H, d,J 2 Hz), 7.39 (1H, dd, J 2+9 Hz), 7.90 (1H, m), 8.14 (2H, m), 8.73 (1H,d, J 7 Hz), 8.97 (1H, d, J 7 Hz), 9.13 (1H, d, J 9 Hz), 10.81 (1H, s),11.09 (1H, s).

m/z (API⁺): 308 (MH⁺).

74. 1-(4-Methoxy-3-prop-2-(enylphenyl)-3-quinolin-4-yl hydrochloride

From 4-methoxy-3-prop-2-enylbenzoic acid (0.251 g) and D4 (0.210 g) thetitle compound (0.092 g) was prepared according to the method of Example50.

¹H NMR δ: 3.33 (2H, d, J 6 Hz), 3.78 (3H, s), 5.08 (2H, m), 5.87-6.01(1H, m), 6.99 (1H, d, J 1Hz), 7.33 (1H, d, J 2 Hz), 7.42 (1H, dd, J 2+9Hz), 7.92 (1H, m), 8.12 (2H, m), 8.73 (1H, d, J 7 Hz), 8.97 (1H, d, J 7Hz), 9.07 (1H, d, J 9 Hz), 10.72 (1H, s), 11.00 (1H, s).

m/z (API⁺): 334 (MH⁺).

75. 1-(3-Ethyl-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride

From 3-ethyl-4-methoxybenzoic acid (0.200 g) and the D4 (0.19 g) thetitle compound (0.160 g) was prepared according to the method of Example50.

¹H NMR δ: 1.15 (3H, t, J 8 Hz), 2.58 (2H, q, J 8 Hz), 3.79 (3H, s), 6.96(1H, d, J 9 Hz), 7.33 (1H, d, J 2 Hz), 7.40 (1H, dd, J 2+9 Hz), 7.91(1H, m), 8.14 (2H, m), 8.74 (1H, d, J 7 Hz), 8.97 (1H, d, J 7 Hz), 9.13(1H, d, J 9 Hz), 10.82 (1H, s), 11.08 (1H, s).

m/z (API⁺): 322 (MH⁺).

76. 1-(3-Acetyl-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride

From 3-acetyl-4-methoxybenzoic acid (0.150 g) and D4 (0.11 g) the titlecompound (0.080 g) was prepared according to the method of Example 50.

¹H NMR δ: 2.56 (3H, s), 3.90 (3H, s), 7.22 (1H, d, J 9 Hz), 7.70 (1H,dd, J 2+9 Hz), 7.80 (1H, d, J 2 Hz), 7.90 (1H, m), 8.14 (2H, m), 8.73(1H, d, J 7 Hz), 8.99 (1H, d, J7 Hz), 9.13 (1H, d, J9 Hz), 11.09 (1H,s), 11.12 (1H, s).

77. 1-(4-Dimethylaminophenyl)-3-(6-fluoroquinolin-4-yl)ureadihydrochloride

From D33 (0.191 g) and N,N-dimethylamino-1,4-benzenediamine (0.136 g)the title compound (0.065 g) was prepared to the method of Example 50.

¹H NMR δ: 3.08 (6H, s), 7.48-7.65 (4H, m), 8.08 (1H, m), 8.28 (1H, dd, J5+9 Hz), 8.75 (1H, d, J 7 Hz), 9.02 (1H, d, J 7 Hz), 9.13 (1H, m), 11.20(2H, s).

m/z (API⁺): 325 (MH⁺).

78. 1-(3,5-Dimethoxyphenyl)-3-quinolin-4-ylurea hydrochloride

D4 (0.14 g) and 3,5-dimethoxphenylisocyanate (0.179 g) were combined indichloromethane (20 ml) and stirred for 16 h. Solvent was removed atreduced pressure, the residue dissolved in methanol and excess etherealHCl added. The precipitated title compound (0.17 g) was collected byfiltration.

¹H NMR δ: 3.75 (6H, s), 6.27 (1H, t, J 2.2 Hz), 6.79 (2H, d, J 2.2 Hz),7.93 (1H, m), 8.08-8.18 (2H, m), 8.73 (1H, d, J 6.8 Hz), 8.98 (1H, d, J6.8 Hz), 9.07 (1H, d, J 5 8.6 Hz), 10.97 (1H, s), 11.03 (1H, s).

m/z (API⁺): 324 (MH⁺).

79. 1-(4-Dimethylaminophenyl)-3-(8-acetylquinolin-4-yl)urea

From D29 (0.420 g) and N,N-dimethylamino-1,4-benzenediamine (0.27 g) thetitle compound (0.135 g) was prepared according to the method of Example50.

¹H NMR δ: 2.76 (3H, s), 3.34 (6H, s), 6.74 (2H, d, J 9 Hz), 7.34 (2H, d,J 9 Hz), 7.75 (2H, m), 8.30 (2H, m), 8.76 (1H, d, J 9 Hz), 9.00 (1H, s),9.24 (1H, s).

m/z (API⁺): 349 (MH⁺).

80. 1-(4-Dimethylaminophenyl)-3-[8-(1-hydroxyethyl)quinolin-4-yl]urea

To a solution of Example 79 (0.090 g) in ethanol/water (15 ml/5 ml) wasadded sodium borohydride (0.040 g). The mixture was stirred under argonat ambient temperature for 16 h. HCl (5M) was added dropwise withice-cooling until effervesence ceased. The mixture was basified withsaturated aqueous Na₂CO₃, the solvents removed at reduced pressure andthe residue triturated with water. The resulting solid was collected byfiltration, trituration with hot ethyl acetate gave the title compound(0.040 g).

¹H NMR δ: 1.44 (3H, d, J 6 Hz), 2.86 (6H, s), 5.33 (1H, bm), 5.81 (1H,bm), 6.74 (2H, d, J 9 Hz), 7.34 (2H, d, J 9 Hz), 7.64 (1H, dd, J 8+8Hz), 7.88 (1H, d, J 8 Hz), 8.14 (1H, d, J 8 Hz), 8.23 (1H, d, J 5 Hz),8.70 (1H, d, J 5 Hz), 9.16 (1H, s), 9.22 (1H, s).

m/z (API⁺): 350 (MH⁺).

81. 1-(4-Dimethylaminophenyl)-3-(8-carboxamidoquinolin-4-yl)urea

To a solution of Example 78 (0.115 g) in dimethylsulfoxide (12 ml) at15° C. was added hydrogen peroxide in water (0.044 ml, 27.85 w/v) andK₂CO₃ (0.072 g). The reaction mixture was heated at 100° C. for 1 h, thedimethyl sulfoxide removed at reduced pressure and water added. Theresulting solid was collected by filtration, trituration with methanolgave the title compound (0.050 g).

¹H NMR δ: 3.35 (6H, s), 6.75 (2H, d, J 9 Hz), 7.35 (2H, d, J 9 Hz), 7.78(1H, dd, J 8+8 Hz), 7.89 (1H, bs), 8.35 (1H, d, J 5 Hz), 8.41 (1H, d, J8 Hz), 8.59 (1H, d, J 8 Hz), 8.81 (1H, d, J 8 Hz), 9.04 (1H, s), 9.30(1H, s), 10.48 (1H, bs).

m/z (API⁺): 350 (MH⁺).

82. 1-(2-Methylbenzoxazol-6-yl)-3-quinolin-4-ylurea hydrochloride

From 2-methyl-6-benzoxazole carboxylic acid (0.150 g) and D4 (0.14 g)the title compound (0.170 g) was prepared according to Example 1, Method3.

¹H NMR (CD₃OD) δ: 2.62 (3H, s), 7.34 (1H, dd, J 2+8 Hz), 7.65 (1H, d, J8 Hz), 8.00 (2H, m), 8.08 (1H, d, J 2 Hz), 8.16 (2H, m), 8.70 (2H, bs),8.76 (1H, d, 7 Hz), 9.02 (1H, d, J 7 Hz).

m/z (API⁺): 319 (MH⁺).

83. 1-Benzoxazol-6-yl-3-quinolin-4-ylurea hydrochloride

From D30 (0.200 g) and D4 (0.14 g) the title compound (0.060 g) wasprepared according to Example 1, Method 3.

1H NMR δ: 7.40 (1H, dd, J 2+9 Hz), 7.90 (1H, d, J 9 Hz), 7.96 (1H, m),8.15 (3H, m), 8.73 (2H, m), 8.92 (1H, d, J 9 Hz), 9.03 (1H, d, J 7 Hz),10.67 (1H, s), 10.92 (1H, s).

84. [3-(3-Quinolin-4-ylureidophenoxy]acetic acid ethyl ester

From D3 (0.13 g) and 3-aminophenoxyacetic acid ethyl ester (0.128 g) thetitle compound (0.036 g), after recrystallisation from methanol/ethylacetate, was prepared according to Example 1, Method 1.

¹H NMR δ: 1.23 (3H, t, J 7.2 Hz), 4.19 (2H, q, J 7.2 Hz), 4.78 (2H, s),6.60 (1H, dd, J 2.1+8.1 Hz), 7.22-7.28 (2H, m), 7.68 (1H, t, J 7.0 Hz),7.78 (1H, t, J 6.9 Hz), 7.99 (1H, d, J 7.5 Hz).

m/z (API⁺): 366 (MH⁺).

85. 1-Quinolin-3-yl-3-quinolin-4-ylurea dihydrochloride

From 4-quinoline carboxylic acid (0.173 g) and 3-aminoquinoline (0.14 g)the title compound (0.055 g) was prepared according to Example 1, Method3.

¹H NMR δ: 7.64-7.74 (2H, m), 7.95 (1H, m), 8.04-8.25 (4H, m), 8.72 (1H,d, J 2 Hz), 8.80 (1H, d, J 7 Hz), 9.08 (2H, m), 9.20 (1H, d, J 9 Hz),11.40 (1H, s), 11.78 (1H, s).

m/z (API⁺): 315 (MH⁺).

86. 1-Benzoxazol-5-yl-3-quinolin-4-ylurea hydrochloride

From D31 (0.200 g) and D4 (0.17 g) the title compound (0.034 g) wasprepared according to Example 1, Method 3.

¹H NMR δ: 7.48 (1H, dd, J 2+9 Hz), 7.78 (1H, d, J 9 Hz), 7.91 (1H, m),8.15 (3H, m), 8.75 (2H, m), 9.00 (1H, d, J 7 Hz), 9.14 (1H, d, J 9 Hz),11.48 (1H, s), 11.32 (1H, s).

m/z (API⁺): 304.

87. 1-(3-Isopropoxyphenyl)-3-quinolin-4-ylurea hydrochloride

From D3 (0.22 g) and 3-isopropoxyaniline (0.07g) the title compound(0.036 g), after recrystallisation from methanol/ethyl acetate, wasprepared according to Example 1, Method 1.

¹H NMR δ: 1.29 (6H, d, J 6.0 Hz), 4.54-4.64 (1H, m), 6.67 (1H, dd, J2.1+8.2 Hz), 7.06 (1H, d, J 8.3 Hz), 7.23-7.29 (2H, m), 7.92 (1H, t, J7.0 Hz), 8.08-8.19 (2H, m), 8.73 (1H, d, J 6.8 Hz), 9.00 (1H, d, J 6.8Hz), 9.13 (1H, d, J 8.6 Hz), 11.06 (1H, s), 11.10 (1H, s).

m/z (API⁺): 322 (MH⁺).

88. 1-(2-Methylbenzoxazol-6-yl)-3-(6-fluoroquinolin-4-yl)ureahydrochloride

From 2-methyl-6-aminobenzoxazole (0.148 g) and D33 (0.191 g) the titlecompound (0.125 g) isolated by filtration, trituration with hot methanoland conversion to the hydrochloride, was prepared according to Example1, Method 3.

¹H NMR δ: 2.61 (3H, s), 7.31 (1H, dd, J 1.95+8.6 Hz), 7.64 (1H, d, J 8.5Hz), 8.01-8.09 (2H, m), 8.23 (1H, dd, J 4.0+9.3 Hz), 8.72 (1H, d, J 6.6Hz), 8.91 (1H, dd, J 2+11 Hz), 9.00 (1H, d, J 6.7 Hz), 10.90 (1H, s),10.97 (1H, s).

m/z (API⁺): 337 (MH⁺).

89. 1-(4-Dimethylaminophenyl)-3-(8-fluoroquinolin-4-yl)ureahydrochloride

From N,N-dimethylbenzene-1,4-diamine (0.178 g) and8-fluoroquinoline-4-carboxylic acid (0.25 g), the title compound (0.036g), after column chromatography and conversion to the hydrochloride, wasprepared according to Example 1, Method 3 usingtoluene/dimethylformamide (2:1) as solvent.

¹H NMR δ: 3.13 (6H, s), 7.58-7.82 (6H, m), 8.05 (1H, dd, J 4.6+8.6 Hz),8.98-9.02 (2H, m), 9.73 (1H, s), 10.37 (1H, s).

m/z (API⁺): 325 (MH⁺).

90. 1-(4-Dimethylaminophenyl)-3-(7-fluoroquinolin-4-yl)ureahydrochloride

From N,N-dimethylbenzene-1,4-diamine (0.178 g) and7-fluoroquinoline-4-carboxylic acid (0.25 g), the title compound (0.036g) after column chromatography and conversion to the hydrochloride, wasprepared according to Example 1, Method 3, using toluene in place ofdimethylformamide as solvent.

¹H NMR δ: 3.09 (6H, s), 7.59-7.67 (4H, m), 7.85-7.93 (1H, m), 7.97 (1H,dd, J 2.5+9.2 Hz), 8.71 (1H, d, J 6.8 Hz), 9.00 (1H, d, J 6.8 Hz), 9.34(1H, m), 11.40 (2H, bs).

m/z (API⁺): 325 (MH⁺).

91. 1-(3-Phenoxyphenyl)-3-quinolin-4-ylurea hydrochloride

From D4 (0.135 g) and 3-phenoxybenzoic acid (0.20 g), the title compound(0.105 g), after column chromatography (silca gel (20% ethylacetate/hexane) conversion to the hydrochloride and recrystallisationfrom methanol, was prepared according to Example 1, Method 3 usingtoluene/dimethylformamide (2:1) in place of dimethylformamide asreaction solvent.

¹H NMR δ: 6.73 (1H, dd, J 1.7+6.2 Hz), 7.06 (2H, dd, J 0.7+6.3 Hz),7.15-7.27 (2H, m), 7.35-7.46 (4H, m), 7.91 (1H, t, J 7.0 Hz), 8.08-8.17(2H, m), 8.68 (1H, d, J 6.8 Hz), 8.97 (1H, d, J 6.8 Hz), 9.09 (1H, d, J8.6 Hz), 11.09 (1H, s), 11.17 (1H, s).

m/z (API⁺): 356 (MH⁺).

92. 1-Quinolin-6-yl-3-quinolin-4-ylurea

From D4 (0.216 g) and 6-aminoquinoline (0.216 g) the title compound(0.06 g) after recrystallisation from methanol was prepared according toExample 1, Method 2.

¹H NMR δ: 7.50 (1H, dd, J 4.2+8.3 Hz), 7.69-7.87 (3H, m), 8.00-8.03 (2H,m), 8.23-8.35 (4H, m), 8.76-8.80 (2H, m), 9.43 (1H, s), 9.68 (1H, s).

m/z (API⁺): 315 (MH⁺).

93. 1-(3-Benzyloxyphenyl)-3-quinolin-4-ylurea hydrochloride

From D3 (0.135 g) and 3-benzyloxyaniline (0.136 g) the title compound(0.139 g), after trituration of the hydrochloride salt with hotmethanol, was prepared according to Example 1, Method 1.

¹H NMR δ: 5.12 (2H, s), 6.77 (1H, dd, J 2.2+8.1 Hz), 7.10 (1H, d, J 7.9Hz), 7.25-7.51 (7H, m), 7.91 (1H, m), 8.08-8.19 (2H, m), 8.73 (1H, d, J6.8 Hz), 9.00 (1H, d, J 6.8 Hz), 9.12 (1H, d, J 8.6 Hz), 11.11 (2H, s).

m/z (API⁺): 370(MH⁺).

94. 1-(2,5-Dimethoxyphenyl)-3-quinolin-4-ylurea

From 2,5-dimethoxyphenyl isocyanate (0.090 g) and D4 (0.072 g) the titlecompound (0.071 g) was prepared according to the method of Example 15.

¹H NMR δ: 3.72 (3H, s), 3.88 (3H, s), 6.57 (1H, dd, J 3.0+8.8 Hz), 6.98(1H, d, J 8.9 Hz), 7.66 (1H, m), 7.78 (1H, m), 7.91 (1H, d, J 3.1 Hz),8.26 (1H, d, J 5.2 Hz), 8.34 (1H, d, J 7.7 Hz), 8.72 (1H, d, J 5.2 Hz),9.16 (1H, s), 9.79 (1H, s).

m/z (API⁺): 324 (MH⁺).

95. 1-(3-Chloro-2-methoxyphenyl)-3-quinolin-4-ylurea

From 3-chloro-2-methoxyphenyl isocyanate (0.092 g) and D4 (0.072 g) thetitle compound (0.03 g), after trituration with pentane/diethyl etherand dichloromethane was prepared according to the method of Example 15.

¹H NMR δ: 3.87 (3H, s), 7.13-7.16 (2H, m), 7.69 (1H, t, J 6.9 Hz), 7.79(1H, t, J 5.8 Hz), 7.99 (1H, d, J 8.3 Hz), 8.21-8.28 (2H, m), 8.32 (1H,d, J 7.6 Hz), 8.74 (1H, d, J 5.1 Hz), 9.37 (1H, s), 9.85 (1H, s).

m/z (API⁺): 328, 330 (MH⁺).

96. 1-(4-Dimethylaminophenyl-3-quinolin-4-ylthiourea dihydrochloride

To D4 (0.144 g) in dimethylformamide (8 ml) sodium hydride (0.05 g, 60%in oil) was added. The mixture was stirred for 30 min and4-dimethylaminophenyl isothiocyanate (0.178 g) added. The mixture wasstirred for 30 min, poured into water and extracted with ethyl acetate(3×50 ml). The combined organic phase was washed with water (2×50 ml),dried (Na₂SO₄), and solvent removed at reduced pressure. The residue wastriturated with diethyl ether/hexane to give the title compound (0.22 g)as the free base which was converted to the dihydrochloride salt (0.235g).

¹H NMR δ: 3.07 (6H, s), 7.42 (2H, bs), 7.77 (2H, d, J 8.1 Hz), 7.93 (1H,t, J 7.5 Hz), 8.14 (1H, t, J 7.0 Hz), 8.26 (1H, d, J 8.4 Hz), 9.02 (3H,m), 11.95 (1H, bs), 12.44 (1H, s).

m/z (API⁺): 323 (MH⁺).

97. 1-(1-Methyl-(1H)-indol-5-yl)-3-(6-methoxy)quinolin-4-ylurea

From 4-amino-6-methoxyquinoline (0.303 g) and5-amino-1-methyl-(1H)-indole (0.255 g) the title compound (0.221 g),after column chromatography (silica gel, hexane→ethyl acetate) andtrituration with diethyl ether, was prepared according to Example 1,Method 2.

¹H NMR δ: 3.96 (3H, s), 4.17 (3H, s), 6.57 (1H, d, J 2.9 Hz), 7.40 (1H,dd, J 1.9+8.8 Hz), 7.49 (1H, d, J 3.0 Hz), 7.57-7.64 (2H, m), 7.72 (1H,d, J 2.4 Hz), 7.98 (1H, d, J 1.7 Hz), 8.08 (1H, d, J 9.2 Hz), 8.38 (1H,d, J 5.1 Hz), 8.75 (1H, d, J 5.1 Hz), 9.17 (1H, bs), 9.26 (1H, bs).

m/z (API⁺): 347 (MH⁺).

98. 1-(3-Methoxyphenyl)-3-quinolin-4-ylurea

From D4 (0.072 g) and 3-methoxyphenyl isocyanate (0.075 g) the titlecompound (0.071 g), was prepared according to the method of Example 12

¹H NMR δ: 3.77 (3H, s), 6.62 (1H, dd, J 1.8 Hz+8.2 Hz), 6.97 (1H, d),7.18-7.24 (2H, m), 7.63-7.68 (1H, m), 7.73-7.78 (1H, m), 7.98 (1H, d),8.17-8.24 (2H, m), 8.74 (1H, d), 9.23 (1H, s), 9.31 (1H, s).

m/z (API⁺): 294 (MH⁺).

99.1-[4-(5-Chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-methylphenyl]-3-quinolin-4-ylurea hydrochloride

From D4 (0.10 g) and N-(4-amino-2-methylphenyl-4-chlorophthalimide(0.199 g) the title compound (0.037 g), after column chromatography(silica gel, hexane→ethyl acetate) salt formation and recrystallisationfrom methanol, was prepared according to Example 1, Method 2.

¹H NMR δ: 2.15 (3H, s), 7.37 (1H, d, J 8.4 Hz), 7.54-7.60 (2H, m),7.91-8.03 (3H, m), 8.08-8.19 (3H, m), 8.75 (1H, d, J 6.8 Hz), 9.01-9.08(2H, m), 11.06 (2H, bs).

m/z (API⁺): 457, 459 (MH⁺).

100. 1-(3-Nitrophenyl)-3-quinolin-4-ylurea

From D4 (0.64 g) and 3-nitrophenyl isocyanate (0.729 g) the titlecompound (0.071 g), after trituration with hot ethanol, was preparedaccording to the method of Example 12.

¹H NMR δ: 7.59-7.85 (4H, m), 7.89 (1H, dd, J 1.4+8.1 Hz), 8.20-8.24 (2H,m), 8.65 (1H, m), 8.76 (1H, d, J 5.1 Hz), 9.37 (1H, s), 9.79 (1H, s).

m/z (API⁺): 309 (MH⁺).

101. 1-(3-Aminophenyl)-3-quinolin-4-ylurea

1-(3-Nitrophenyl)-3-quinolin-4-ylurea (0.775 g) was suspended in ethanol(150 ml) containing 10% Pd/C (0.75 g paste) and shaken under a hydrogenatmosphere (50 psi) at room temperature. After 3 h the mixture wasfiltered (celite pad) and the residue washed with ethanol. The combinedfiltrate and washings were evaporated to dryness under reduced pressureand the residue triturated with diethyl ether/hexane to give the titlecompound (0.54 g).

¹H NMR δ: 5.13 (2H, s), 6.26 (1H, d, J 7.8 Hz), 6.65 (1H, d, J 7.8 Hz),6.83 (1H, s), 6.95 (1H, t, J 7.9 Hz), 7.67 (1H, t, J 7.0 Hz), 7.77 (1H,t, J 6.9 Hz), 7.97 (1H, d, J 8.0 Hz), 8.19-8.25 (2H, m), 8.71 (1H, d, J5.2 Hz), 9.09 (1H, bs), 9.16 (1H, bs).

m/z (API⁺): 279 (MH⁺).

102. N-[3-(3-Quinolin-4-ylureido)phenyl]methanesulphonamide

Methanesulphonyl chloride (27 ul) was added to1-(3-aminophenyl)-3-quinolin-4-ylurea (0.08 g) in dichloromethane (25ml) containing triethylamine (48 ul) and stirred for 16 h. Theprecipitate that formed was separated by filtration, washed withtetrahydrofuran and diethyl ether and dried to give the title compound(0.081 g).

¹H NMR δ: 3.03 (3H, s), 6.93-6.98 (1H, m), 7.33-7.35 (2H, m), 7.52 (1H,s), 7.95 (1H, m), 8.04-8.14 (2H, m), 8.66 (1H, d), 8.75 (1H, d), 8.99(1H, d), 9.86 (1H, s), 10.35 (1H, s), 10.55 (1H, s).

m/z (API⁺): 357 (MH⁺).

Determination of HFGAN72 Receptor Antagonist Activity

The HFGAN72 receptor antagonist activity of the compounds of formula(I), including those compounds in which X and Y both represent CH andwithout provisos a)-f), was determined in accordance with the followingexperimental method.

Experimental Method

HEK293 cells expressing the human HFGAN72 receptor were grown in cellmedium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calfserum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/wellinto 96-well black clear bottom sterile plates from Costar which hadbeen pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seededplates were incubated overnight at 37° C. in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC₅₀ values(the concentration required to produce 50% maximal response) wereestimated using 11× half log unit dilutions (Biomek 2000, Beckman) inTyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5 mMprobenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO(100%). Antagonist IC₅₀ values (the concentration of compound needed toinhibit 50% of the agonist response) were determined against 3.0 nMhuman Lig 72A using 11× half log unit dilutions in Tyrode's buffercontaining 10% DMSO and probenecid. On the day of assay 50 μl of cellmedium containing probenecid (Sigma) and Fluo3AM (Texas FluorescenceLaboratories) was added (Quadra, Tomtec) to each well to give finalconcentrations of 2.5 mM and 4 μM, respectively. The 96-well plates wereincubated for 90 min at 37° C. in 5% CO₂. The loading solutioncontaining dye was then aspirated and cells were washed with 4×150 μlTyrode's buffer containing probenecid and 0.1% gelatin (Denley CellWash). The volume of buffer left in each well was 125 μl. Antagonist orbuffer (25 μl) was added (Quadra) the cell plates gently shaken andincubated at 37° C. in 5% CO₂ for 30 min. Cell plates were thentransferred to the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices) instrument and maintained at 37° C. in humidified air. Prior todrug addition a single image of the cell plate was taken (signal test),to evaluate dye loading consistency. The run protocol used 60 imagestaken at 1 second intervals followed by a further 24 images at 5 secondintervals. Agonists were added (by the FLIPR) after 20 sec (duringcontinuous reading). From each well, peak fluorescence was determinedover the whole assay period and the mean of readings 1-19 inclusive wassubtracted from this figure. The peak increase in fluorescence wasplotted against compound concentration and iteratively curve fittedusing a four parameter logistic fit (as described by Bowen and Jerman,1995, TiPS, 16, 413-417) to generate a concentration effect value.Antagonist Kb values were calculated using the equation:

K _(b) =IC ₅₀/(1+([3/EC ₅₀])

where EC₅₀ was the potency of human Lig72A determined in the assay (innM terms) and IC₅₀ is expressed in molar terms.

As an illustration of the activity of the compounds of formula (I), thecompounds of Examples 1, 14, 17 and 31 each had a pKb>7 in this assay.

What is claimed is:
 1. A compound of formula (I):

in which: X and Y independently represent CH or nitrogen, provided thatX and Y do not both represent CH; Z represents oxygen or sulphur; R¹represents (C₁₋₆)alkyl, (C₂₋₆)alkenyl or (C₁₋₆)alkoxy, any of which maybe optionally substituted; halogen, R⁷CO— or NR⁸R⁹CO—; R², R³, R⁴, R⁵and R⁶ independently represent (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₁₋₆)alkoxyor (C₁₋₆)alkylthio, any of which may be optionally substituted;hydrogen, halogen, nitro, cyano, aryloxy, aryl(C₁₋₆)alkyloxy,aryl(C₁₋₆)alkyl, R⁷CO—, R⁷SO₂NH—, R⁷CON(R¹⁰)—, NR⁸R⁹—, NR⁸R⁹CO—, —COOR⁸or heterocyclyl; provided that at least one of R², R³, R⁴, R⁵ and R⁶ isother than hydrogen; or an adjacent pair of R², R³, R⁴, R⁵ and R⁶together with the carbon atoms to which they are attached form anoptionally substituted carbocyclic or heterocyclic ring; R⁷ is(C₁₋₆)alkyl or aryl; R⁸ and R⁹ independently represent hydrogen,(C₁₋₆)alkyl, aryl or aryl(C₁₋₆)alkyl; R¹⁰ is hydrogen or (C₁₋₆)alkyl;and n is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof;provided that the compound is not: a)N-1-isoquinolinyl-N′-(1-methyl-1H-indol-5-yl)urea; b)N-(3-chloro-4-trifluoromethylphenyl)-N′-4-quinolinylurea; c)N-(3-chloro-4-trifluoromethylphenyl)-N′-(5-nitro-4-quinolinyl)urea; d)N-(3,4,5-trimethoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea; e)N-(4-methoxyphenyl)-N′-(7-chloro-4-quinolinyl)urea; or f)N-(4-chlorophenyl)-N′-(7-chloro-4-quinolinyl)urea.
 2. A compoundaccording to claim 1, in which X represents CH and Y representsnitrogen.
 3. A compound according to claim 1, in which Z representsoxygen.
 4. A compound according to claim 1, in which n is 0 or
 1. 5. Acompound according to claim 1, in which R² to R⁶ independently representhydrogen, halogen, (C₁₋₆)alkoxy, (C₁₋₆)alkylthio or NR⁸R⁹, and at leastone of R² to R⁶ is other than hydrogen; or an adjacent pair of R² to R⁶together with the carbon atoms to which they are attached form anoptionally substituted 5- to 7-membered heterocyclic ring.
 6. A compoundaccording to claim 1 in which R², R⁵ and R⁶ represent hydrogen.
 7. Acompound according to claim 1 in which R², R⁴ and R⁶ represent hydrogen.8. A compound according to claim 1 selected from:1-(1-methyl-1H-indol-5-yl)-3-quinolin-4-ylurea,1-(1-methyl-1H-indol-5-yl)-3-quinolin-4-yl)urea hydrochloride,1-(1-ethyl-1H-indol-5-yl)-3-quinolin-4-ylurea,1-[1-(3-phenylpropyl)-1H-indol-5-yl]-3-quinolin-4-ylurea,1-(1-benzyl-1-H-indol-5-yl)-3-quinolin-4-ylurea,1-[1-(3-carboethoxypropyl)-1H-indol-5-yl]-3-quinolin-4-ylurea,1-[1-(3-cyanopropyl)-1H-indol-5-yl]-3-quinolin-4-ylurea hydrochloride,1-(1H-indol-5-yl)-3-quinolin-4-ylurea,1-(1-methyl-1H-indolin-5-yl)-3-quinolin-4-ylurea,1-(1-methyl-1-(1H-indolin-5-yl)-3-quinolin-4-ylurea dihydrochloride,1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-quinolin-4-ylurea hydrochloride,1-benzo[1,3]dioxol-5-yl-3-quinolin-4-ylurea hydrochloride,1-(4-methoxyphenyl)-3-quinolin-4-ylurea,1-(3-methylthiophenyl)-3-quinolin-4-ylurea hydrochloride,1-(3,4-dimethoxyphenyl)-3-quinolin-4-ylurea,1-(4-methylthiophenyl)-3-quinolin-4-ylurea hydrochloride,1-(3-ethylphenyl)-3-quinolin-4-ylurea,1-(4-ethoxyphenyl)-3-quinolin-4-ylurea,1-(4-N,N-dimethylaminophenyl)-3-quinolin-4-ylurea,1-(4-N,N-dimethylaminophenyl)-3-quinolin-4-ylurea dihydrochloride,1-(4-carboethoxyphenyl)-3-quinolin-4-ylurea,1-(4-n-butylphenyl)-3-quinolin-4-ylurea,1-(4-ethylphenyl)-3-quinolin-4-ylurea,1-(4-trifluoromethoxyphenyl)-3-quinolin-4-ylurea,1-(4-chlorophenyl)-3-quinolin-4-ylurea,1-(3-chlorophenyl)-3-quinolin-4-ylurea,1-(3-chloro-4-methylphenyl)-3-quinolin-4-ylurea,1-(3-cyanophenyl)-3-quinolin-4-ylurea,1-(3,4-dichlorophenyl)-3-quinolin-4-ylurea,1-(3-carboethoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(3-bromo-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(4-trifluoromethylthiophenyl)-3-quinolin-4-ylurea hydrochloride,1-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-3-quinolin-4-ylureahydrochloride, 1-(3-chloro-4-methoxyphenyl)-3-quinolin-4-ylureahydrochloride, 1-(4-N-morpholin-4-ylphenyl)-1-quinolin-4-ylureadihydrochloride, 1-(3-acetylphenyl)-3-quinolin-4-ylurea hydrochloride,1-(4-phenylaminophenyl)-3-quinolin-4-ylurea dihydrochloride,1-[3-(1,3-oxazo-5-yl)phenyl]-3-quinolin-4-ylurea,1-[4-((4,6-dimethylpyrimidin-2-yl)methylamino)phenyl]-3-quinolin-4-ylureadihydrochloride, 1-(4-pyrrolidinylphenyl)-3-quinolin-4-ylureadihydrochloride, 1-(3-dimethylaminophenyl)-3-quinolin-4-ylureadihydrochloride, 1-(4-carboxamidophenyl)-3-quinolin-4-ylureahydrochloride, 1-(4-N,N-diethylaminophenyl)-3-quinolin4-ylureadihydrochloride,1-(4-dimethylaminophenyl)-3-(5-methoxyquinolin-4-yl)ureadihydrochloride, 1-(4-dimethylaminophenyl)-3-(8-bromoquinolin-4-yl)ureadihydrochloride,1-(4-dimethylaminophenyl)-3-(8-methoxyquinolin-4-yl)ureadihydrochloride, 1-(2-chlorophenyl)-3-quinolin-4-ylurea,1-(2-methylphenyl)-3-quinolin-4-ylurea,1-(4-methoxy-2-methylphenyl)-3-quinolin-4-ylurea hydrochloride,1-(1-hydroxy-1-ethylphen-3-yl)-3-quinolin-4-ylurea hydrochloride,1-(3-trifluoromethylthiophenyl)-3-quinolin-4-ylurea hydrochloride,1-(3,5-dichlorophenyl)-3-quinolin-4-ylurea hydrochloride,1-(1-methylbenzimidazol-6-yl)-3-quinolin-4-ylurea dihydrochloride,1-(4-methoxy-3-trifluoromethylphenyl)-3-quinolin-4-ylurea hydrochloride,N-methyl-3-(3-quinolin-4-ylureido)benzamide hydrochloride,1-(4-dimethylaminomethylphenyl)-3-quinolin-4-ylurea dihydrochloride,1-(4-hydroxymethylphenyl)-3-quinolin-4-ylurea hydrochloride,1-(4-N,N-dimethylaminophenyl)-3-(7-methoxy)quinolin-4-ylureahydrochloride, 1-(3-fluoro-4-methoxyphenyl)-3-quinolin-4-ylureahydrochloride,1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-3-quinolin-4-ylureahydrochloride, 1-(3-chloro-4-dimethylaminophenyl)-3-quinolin-4-ylureadihydrochloride, 1-quinolin-4-yl-3-(4-[1,2,4]triazol-1-ylphenyl) ureahydrochloride, 1-(benzothiazol-6-yl)-3-quinolin-4-ylurea hydrochloride,1-benzo[b]thiophen-5-yl-3-quinolin-4-ylurea hydrochloride,1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-quinolin-4-ylureadihydrochloride,1-(4-N-ethyl-N-isopropylaminophenyl)-3-quinolin-4-ylureadihydrochloride,1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-3-quinolin-4-ylureadihydrochloride,1-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-3-quinolin-4-yl ureahydrochloride, 1-(1,2-dimethyl-1H-indol-5-yl)-3-quinolin-4-ylureahydrochloride, 1-(2,3-dihydro-1H-indol-5-yl)-3-quinolin-4-yl ureadihydrochloride, 1-(4-dimethylaminophenyl)-3-(7-bromoquinolin-4-yl)ureadihydrochloride, 1-(4-dimethylaminophenyl)-3-(6-bromoquinolin-4-yl)ureadihydrochloride, 1-(3-ethoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(4-ethylthiophenyl)-3-quinolin-4-yl urea hydrochloride,1-(3-bromo-4-dimethylaminophenyl)-3-quinolin-4-ylurea-dihydrochloride,1-(4-methoxy-3-methylphenyl)-3-quinolin-4-ylurea hydrochloride,1-(4-methoxy-3-prop-2-enylphenyl)-3-quinolin-4-yl hydrochloride,1-(3-ethyl-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(3-acetyl-4-methoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(4-dimethylaminophenyl)-3-(6-fluoroquinolin-4-yl)urea dihydrochloride,1-(3,5-dimethoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(4-dimethylaminophenyl)-3-(8-acetylquinolin-4-yl)urea,1-(4-dimethylaminophenyl)-3-[8-(1-hydroxyethyl)quinolin-4-yl]urea,1-(4-dimethylaminophenyl)-3-(8-carboxamidoquinolin-4-yl)urea,1-(2-methylbenzoxazol-6-yl)-3-quinolin-4-ylurea hydrochloride,1-benzoxazol-6-yl-3-quinolin-4-ylurea hydrochloride,[3-(3-quinolin-4-ylureidophenoxy]acetic acid ethyl ester,1-quinolin-3-yl-3-quinolin-4-ylurea dihydrochloride,1-benzoxazol-5-yl-3-quinolin-4-ylurea hydrochloride,1-(3-isopropoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(2-methylbenzoxazol-6-yl)-3-(6-fluoroquinolin-4-yl)urea hydrochloride,1-(4-dimethylaminophenyl)-3-(8-fluoroquinolin-4-yl)urea hydrochloride,1-(4-dimethylaminophenyl)-3-(7-fluoroquinolin-4-yl)urea hydrochloride,1-(3-phenoxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-quinolin-6-yl-3-quinolin-4-ylurea,1-(3-benzyloxyphenyl)-3-quinolin-4-ylurea hydrochloride,1-(2,5-dimethoxyphenyl)-3-quinolin-4-ylurea,1-(3-chloro-2-methoxyphenyl)-3-quinolin-4-ylurea,1-(4-dimethylaminophenyl)-3-quinolin-4-ylthiourea dihydrochloride,1-(1-methyl-(1H)-indol-5-yl)-3-(6-methoxy)quinolin-4-ylurea,1-(3-methoxyphenyl)-3-quinolin-4-ylurea,1-[4-(5-chloro-1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-methylphenyl]-3-quinolin-4-ylurea hydrochloride, 1-(3-nitrophenyl)-3-quinolin-4-ylurea,1-(3-aminophenyl)-3-quinolin-4-ylurea, andN-[3-(3-quinolin-4-ylureido)phenyl]methanesulphonamide.
 9. A process forthe preparation of a compound of formula (I) as defined in claim 1 or asalt thereof which comprises coupling a compound of formula (II):

with a compound of formula (III):

where A and B are appropriate functional groups to form the —NHCONH— or—NHCSNH— moiety when coupled; X, Y and n are as defined in formula (I);and R^(1′) to R^(6′) are R¹ to R⁶ as defined in formula (I) or groupsconvertible thereto; and thereafter optionally and as necessary and inany appropriate order, converting any R^(1′) to R^(6′) when other thanR¹ to R⁶ respectively to R¹ to R⁶, and/or forming a pharmaceuticallyacceptable salt thereof.
 10. A pharmaceutical composition comprising acompound of formula (I) as defined in claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.
 11. Amethod of treating or preventing diseases or disorders where anantagonist of the human HFGAN72 receptor is required, which comprisesadministering to a subject in need thereof an effective amount of acompound of formula (I), according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 12. A method of treating or preventing diseasesor disorders where an antagonist of the human HFGAN72 receptor isrequired, which comprises administering to a subject in need thereof aneffective amount of a compound of formula (I) according to claim 8.